If cancer can be detected before metastasis and completely removed by surgery then effectively it can be cured. Also, the earlier stage detection allows treatments a higher chance of success because at earlier stage the cancers have developed fewer defensive mutations against chemo agents. Well, a couple of Kansas State researchers have developed a blood test that works before clinical symptoms for two major cancers with a test for pancreatic cancer coming soon.
In less than an hour, the test can detect breast cancer and non-small cell lung cancer -- the most common type of lung cancer -- before symptoms like coughing and weight loss start. The researchers anticipate testing for the early stages of pancreatic cancer shortly.
The test was developed by Stefan Bossmann, professor of chemistry, and Deryl Troyer, professor of anatomy and physiology. Both are also researchers affiliated with Kansas State University's Johnson Cancer Research Center and the University of Kansas Cancer Center. Gary Gadbury, professor of statistics at Kansas State University, helped analyze the data from tests with lung and breast cancer patients. The results, data and analysis were recently submitted to the Kansas Bio Authority for accelerated testing.
When early stage blood tests for cancer detection become available it would help if we did not have to go to a doctor's office during normal business hours to get these tests done. One should be able to go to a pharmacy after work, or even at quarterly sessions at bigger businesses, to give blood for early stage disease detection tests. When tests become much more powerful and beneficial they should become far easier to get done.
Imagine detection of cancer at stage 0.
A blood sample from each participant was tested three times. Analysis of the data showed a 95 percent success rate in detecting cancer in participants, including those with breast cancer in stages 0 and 1 and those with lung cancer in stages 1 and 2.
Really early stage detection will bring with it the problem of finding the cancer. The smaller it is the harder it'll be to locate.
Some Moffitt Cancer Center researchers have written an opinion piece on the key role that evolution plays in allowing cancers to adapt to new therapies aimed at wiping it out.
While targeted therapies have been among the most recent approaches to treating cancer, the authors suggest that the vast changes in the genetics of tumors via mutations reduce the effectiveness of targeted therapies and are a reason why targeted therapies cease to work.
"The emergence of resistance is predictable and inevitable as a fundamental property of carcinogenesis," Gatenby said. "However, this fundamental fact is commonly ignored in the design of treatment strategies. The emergence of drug resistance is rarely, if ever, dealt with until it occurs."
Since cancers are genetically very heterogeneous and they mutate at a fast rate drugs aimed at cancers very often fail to wipe out some small number of cancer cells that have mutations that enable them to survive. Then the small number of survivors starts multiplying to fill in niches left by the cancer cells killed by a therapy. Rather quickly a therapy ceases to work and the cancer comes back full force.
The researchers speculate that cancer cells can be directed to evolve in ways that make it easier to prevent resistance. I find this wishful thinking.
In an effort to develop patient-specific, long-term therapeutic strategies, the authors contend that resistance should be anticipated. By "anticipation" in action, they mean developing "adaptive therapies" prior to the emergence of resistance.
Cancer cells, they wrote, can only adapt to immediate selection forces. Cancer cells cannot anticipate future environmental conditions or evolutionary dynamics. This concept, said the authors, may provide an advantage when designing new therapies by "directing" the natural selection processes to prevent the outgrowth of resistant cancer populations and so improve outcomes.
How will cancer be defeated? One way I can see is to develop many very effective therapies that each use a different mechanism. Then deliver them all at once. The odds of all cancer cells containing mutations to resist many therapies goes down if the therapies are delivered in parallel rather than serially. In time we'll get many more therapies. I expect this approach to work eventually, especially with therapies which have low toxicity to normal cells..
There is, however, a way to harness cancer's ability to evolve drug resistance against it: Use therapies that cause cancer cells to select for up-regulating genes that make the cells much more vulnerable to classes of toxins or monoclonal antibodies. Basically, make it evolutionarily adaptive for cancer cells to set themselves up for a fall.
For example, provide cancers with a chemical compound that becomes beneficial to them if the cancers up-regulate some enzyme that converts the compound into a source of food. Once the cancer cells have up-regulated the enzyme then give them a different chemical compound that the same enzyme will convert into a toxin.
CAMBRIDGE, Mass. -- One of the biggest risk factors for liver, colon or stomach cancer is chronic inflammation of those organs, often caused by viral or bacterial infections. A new study from MIT offers the most comprehensive look yet at how such infections provoke tissues into becoming cancerous.
The study, which is appearing in the online edition of Proceedings of the National Academy of Sciences the week of June 11, tracked a variety of genetic and chemical changes in the livers and colons of mice infected with Helicobacter hepaticus, a bacterium similar to Helicobacter pylori, which causes stomach ulcers and cancer in humans.
What I wonder: How much cancer could be prevented if we all got tested for chronic infections and got treated for any infections found? Or could a round of antibiotics without even first testing for a bacterial infection cut cancer risks?
The immune system generates toxic chemicals to kill bacteria. But those toxic chemicals also damage tissue in ways that can lead to cancer.
In the colon, but not the liver, neutrophils secreted hypochlorous acid (also found in household bleach), which significantly damages proteins, DNA and RNA by adding a chlorine atom to them. The hypochlorous acid is meant to kill bacteria, but it also leaks into surrounding tissue and damages the epithelial cells of the colon. The researchers found that levels of one of the chlorine-damage products in DNA and RNA, chlorocytosine, correlated well with the severity of the inflammation, which could allow them to predict the risk of chronic inflammation in patients with infections of the colon, liver or stomach. Tannenbaum recently identified another chlorine-damage product in proteins: chlorotyrosine, which correlates with inflammation. While these results point to an important role for neutrophils in inflammation and cancer, "we don't know yet if we can predict the risk for cancer from these damaged molecules," Dedon says.
Unfortunately, we live in a time when drug resistant strains of tuberculosis, gonorrhoea, and other bacteria are spreading globally. Be careful. Bacteria should be taken as a serious threat to health once again.
Chromosomal deletions in DNA often involve just one of two gene copies inherited from either parent. But scientists haven't known how a deletion in one gene from one parent, called a "hemizygous" deletion, can contribute to cancer.
A research team led by Stephen Elledge, a professor in the Department of Genetics at Harvard Medical School, and his post-doctoral fellow Nicole Solimini, has now provided an answer. The most common hemizygous deletions in cancer, their research shows, involve a variety of tumor suppressing genes called STOP genes (suppressors of tumorigenesis and proliferation) that scatter randomly throughout the genome, but that sometimes cluster in the same place on a chromosome. And these clusters, said Elledge, who is also a professor of medicine at Brigham and Women's Hospital, tend to be deleted as a group. "Eliminating the cluster gives a bigger bang for the deletion buck," he said.
So I've got a modest proposal for genetically reegineering the human genome to reduce the risk of cancer: make big deletions of multiple oncogenes lethal for the cell. How? Mix absolutely essential genes in between the oncogenes. If the oncogenes get deleted in a big block then the cell should die due to loss of essential genes. Basically, do genetic layout so those big deletion mutations are lethal.
Your new word for the day: haploinsufficient. Try to mix it into everyday conversation.
This finding is especially interesting in light of the two-hit model of cancer formation, which holds that both copies of a recessive gene need to be inactivated to trigger a biological effect. Thus the loss of a single tumor suppressor copy should have little or no influence on tumor cell proliferation because the remaining copy located on the other chromosome is there to pick up the slack.
Elledge's research points to a different hypothesis, namely that STOP genes in a hemizygous deletion aren't recessive but are instead haploinsufficient, meaning that they depend on two copies to function normally. "If a tumor suppressor is haploinsufficient, then a single gene copy lacks the potency needed to fully restrain tumorigenesis," Elledge explained, who is also a Howard Hughes Medical Institute Investigator. "So by removing clusters of haploinsufficient genes all at once, the cancer cell immediately propels its growth forward without having to wait for the other copies to also be lost."
Perhaps 10 or 20 years hence stem cells intended for therapies will get genetically enhanced to be far less susceptible to mutations that could turn them cancerous. My rearranging the genome the number of mutations needed to make a cancerous cell could be greatly increased, with cells becoming more likely to die than become cancerous when they lose genes involved in protection against cancer.
Since some rare people have immune systems which aggressively attack cancers we should also figure out what makes their genomes better in this regard. Then we should develop gene therapies and cell therapies that enhance our immune systems to snuff out early stage cancers.
STANFORD, Calif. — The cells that slough off from a cancerous tumor into the bloodstream are a genetically diverse bunch, Stanford University School of Medicine researchers have found. Some have genes turned on that give them the potential to lodge themselves in new places, helping a cancer spread between organs. Others have completely different patterns of gene expression and might be more benign, or less likely to survive in a new tissue. Some cells may even express genes that could predict their response to a specific therapy. Even within one patient, the tumor cells that make it into circulating blood vary drastically.
The finding underscores how multiple types of treatment may be required to cure what appears outwardly as a single type of cancer, the researchers say. And it hints that the current cell-line models of human cancers, which showed patterns that differed from the tumor cells shed from human patients, need to be improved upon.
The new study, which will be published online May 7 in PLoS ONE, is the first to look at so-called circulating tumor cells one by one, rather than taking the average of many of the cells. And it's the first to show the extent of the genetic differences between such cells.
I do not find this at all surprising. A tumor has large numbers cells undergoing rapid division and more mutations happen in each cell division. Many of those cancer cells are sick and dying, making room for cells with mutations that provide advantages for spreading. Natural selection operates very strongly for cancer cells which secrete more angiogenesis factors to promote blood vessel growth needed for tumor growth, which secrete factors that dampen immune response against them, and which have greater ability to move around in the blood stream and land in other parts of the body and divide. So a tumor becomes genetically very diverse.
What's more interesting: the tools used to do the study. Those tools will some day help to identify all the important genetic subpopulations of cancer cells in each cancer patient.
First the researchers used a technology they developed to separate the literally 1-in-a-million circulating tumor cells (CTCs) from normal blood cells.
To make their latest discovery, Jeffrey, along with an interdisciplinary team of engineers, quantitative biologists, genome scientists and clinicians, relied on a technology they developed in 2008. Called the MagSweeper, it's a device that lets them isolate live CTCs with very high purity from patient blood samples, based on the presence of a particular protein — EpCAM — that's on the surface of cancer cells but not healthy blood cells.
Then they used microfluidic chips to look at each individual cancer cells.
So once Jeffrey and her collaborators isolated CTCs using the MagSweeper, they turned to a different kind of technology: real-time PCR microfluidic chips, invented by a Stanford collaborator, Stephen Quake, PhD, professor of bioengineering. They purified genetic material from each CTC and used the high-throughput technology to measure the levels of all 95 genes at once. The results on the cell-line-derived cells were a success; the genes in the CTCs reflected the known properties of the mouse cell-line models. So the team moved on to testing the 95 genes in CTCs from 50 human breast cancer patients — 30 with cancer that had spread to other organs, 20 with only primary breast tumors.
To defeat cancer we need cheap and highly powerful microfluidic devices to identify every trick each cancer is using to survive and spread. While in this study only at most 5 individual CTCs were analyzed in the future costs will drop. Cheaper microfluidic devices will enable analysis of many more CTCs per patient yielding more detailed analyses.
Next we need microfluidic devices that can construct agents (e.g. gene therapies, antibodies, specialized immune cells) that will target each of the cancer subpopulations.
Even better: Imagine early stage cancer detection by periodic blood tests fed into very microfluidic devices installed in a fully automated home medical test lab. Earlier stage discovery brings the advantage that the cancer hasn't yet mutated adaptations for metastasis.
Cancer death rates declined much more rapidly than cancer incidence. One possible interpretation: treatments are becoming more effective.
ATLANTA – January 4, 2012 – The American Cancer Society's annual cancer statistics report shows that between 2004 and 2008, overall cancer incidence rates declined by 0.6% per year in men and were stable in women, while cancer death rates decreased by 1.8% per year in men and by 1.6% per year in women.
Progress is slowly being made across a range of different cancers.
Death rates continue to decline for all four major cancer sites (lung, colorectum, breast, and prostate), with lung cancer accounting for almost 40% of the total decline in men and breast cancer accounting for 34% of the total decline in women.
One of the next weapons against cancer: whole genome sequencing. The hope is that anti-cancer treatments can be customized to aim at identifying and then counteracting the combination of mutations that enable each specific cancer. Multiple research efforts are each sequencing hundreds of cancer genomes. A company called Complete Genomics will sequence cancer and normal genomes of a cancer patient for $12,000 and already have hundreds of customers.
A total of about 30,000 human genomes were sequenced in 2011, an order of magnitude more than were sequenced in 2010. This is due to the very rapid rate of decline in costs of sequencing DNA. So we are just at the beginning of a huge flood of genetic sequencing data.
Since some (if not all) cancer happens due to genetic mutations the flood of genetic data ought to provide major clues on how to defeat cancer. Since each cancer has many unique mutations sorting thru them is very non-trivial. Even once more cancer-enabling mutations are identified developing treatments that target them will take years. So I'm not expecting a big short-term payoff.
(PHILADELPHIA) -- In a cancer treatment breakthrough 20 years in the making, researchers from the University of Pennsylvania's Abramson Cancer Center and Perelman School of Medicine have shown sustained remissions of up to a year among a small group of advanced chronic lymphocytic leukemia (CLL) patients treated with genetically engineered versions of their own T cells. The protocol, which involves removing patients' cells and modifying them in Penn's vaccine production facility, then infusing the new cells back into the patient's body following chemotherapy, provides a tumor-attack roadmap for the treatment of other cancers including those of the lung and ovaries and myeloma and melanoma. The findings, published simultaneously today in the New England Journal of Medicine and Science Translational Medicine, are the first demonstration of the use of gene transfer therapy to create "serial killer" T cells aimed at cancerous tumors.
It worked fast and better than expected.
"Within three weeks, the tumors had been blown away, in a way that was much more violent than we ever expected," said senior author Carl June, MD, director of Translational Research and a professor of Pathology and Laboratory Medicine in the Abramson Cancer Center, who led the work. "It worked much better than we thought it would."
A big improvement over existing treatments.
The results of the pilot trial of three patients are a stark contrast to existing therapies for CLL. The patients involved in the new study had few other treatment options. The only potential curative therapy would have involved a bone marrow transplant, a procedure which requires a lengthy hospitalization and carries at least a 20 percent mortality risk -- and even then offers only about a 50 percent chance of a cure, at best.
They targeted a protein on the surface of cancer cells called CD19 and they are now going to go after more cancers.
Moving forward, the team plans to test the same CD19 CAR construct in patients with other types of CD19-positive tumors, including non-Hodgkin's lymphoma and acute lymphocytic leukemia. They also plan to study the approach in pediatric leukemia patients who have failed standard therapy. Additionally, the team has engineered a CAR vector that binds to mesothelin, a protein expressed on the surface of mesothelioma cancer cells, as well as on ovarian and pancreatic cancer cells.
What I do not understand: Normal B cells in the blood also express CD19. So what happens with all the healthy B cells? How can a patient survive without them?
Any cancer with unique surface proteins is potentially targetable via this therapy. So the question in my mind: Do all cancers have unique surface proteins? Otherwise a therapy could wipe out a needed type of tissue.
Sam W. Lee and Anna Mandinova of Massachusetts General Hospital have accidentally discovered a compound that kills cancer cells by suppressing enzymes that detoxify free radicals.
A cancer cell may seem out of control, growing wildly and breaking all the rules of orderly cell life and death. But amid the seeming chaos there is a balance between a cancer cell's revved-up metabolism and skyrocketing levels of cellular stress. Just as a cancer cell depends on a hyperactive metabolism to fuel its rapid growth, it also depends on anti-oxidative enzymes to quench potentially toxic reactive oxygen species (ROS) generated by such high metabolic demand.
Scientists at the Broad Institute and Massachusetts General Hospital (MGH) have discovered a novel compound that blocks this response to oxidative stress selectively in cancer cells but spares normal cells, with an effectiveness that surpassed a chemotherapy drug currently used to treat breast cancer. Their findings, based on experiments in cell culture and in mice, appear online in Nature on July 13.
The plant-based compound piperlongumine (PL), derived from the fruit of a pepper plant found in southern India and southeast Asia, appears to kill cancer cells by jamming the machinery that dissipates high oxidative stress and the resulting ROS. Normal cells have low levels of ROS, in tune with their more modest metabolism, so they don't need high levels of the anti-oxidant enzymes that PL stymies once they pass a certain threshold.
Cancer cells generate a lot more toxic reactive oxygen species (ROS) because cancer cells grow at a fast rate. Cancer cells have faster rates of metabolism. So a drug that inhibits the cell's defenses against ROS will selectively cause much higher ROS concentration in cancer cells than in normal cells.
Since normal cells do not generate ROS in quantities that are immediately toxic the drug appears to be highly selective for cancer cells.
The scientists tested PL against cancer cells and normal cells engineered to develop cancer. In mice injected with human bladder, breast, lung, or melanoma cancer cells, PL inhibited tumor growth but showed no toxicity in normal mice. In a tougher test of mice that developed breast cancer spontaneously, PL blocked both tumor growth and metastasis. In contrast, the chemotherapy drug paclitaxel (Taxol) was less effective, even at high levels.
"This compound is selectively reducing the enzyme activity involved in oxidative stress balance in cancer cells, so the ROS level can go up above the threshold for cell death," said Lee, a Broad associate member and associate director of CBRC at MGH. "We hope we can use this compound as a starting point for the development of a drug so patients can benefit."
It'll probably be years before this drug (or drugs like it) get tried in humans in clinical trials. But since this compound is found in pepper plants it might be possible to get the compound outside of medical channels of distribution. If I had fatal cancer I would try to get some of it to try.blockquote>
One problem with gene therapy is how to deliver the genes. The immune system will react to gene carrier packages, the liver potentially could filter out the gene therapy packages, and genes usually should go to only a small number of cell types and organs Packaging gene therapy into microbubbles enables better control and success for delivering gene therapy into cancer cells in prostates.
Richmond, Va. (May 10, 2011) – Cancer researchers are a step closer to finding a cure for advanced prostate cancer after effectively combining an anti-cancer drug with a viral gene therapy in vivo using novel ultrasound-targeted microbubble-destruction (UTMD) technology. The research was conducted by scientists at Virginia Commonwealth University Massey Cancer Center, VCU Institute of Molecular Medicine and School of Medicine, in collaboration with colleagues from Washington University School of Medicine and Sanford-Burnham Medical Research Institute.
In their study, published in the journal Proceedings of the National Academy of Sciences, prostate cancer growth in mice with functioning immune systems was inhibited by sensitizing the cancer cells with the drug Sabutoclax (BI-97C1) and using UTMD technology to deliver a viral gene therapy that expresses the gene mda-7/IL-24. This powerful new approach to treating prostate cancer builds upon prior studies by principle investigator Paul B. Fisher, M.Ph., Ph.D., Thelma Newmeyer Corman Endowed Chair at VCU Massey, professor and chair of the Department of Human and Molecular Genetics in the VCU School of Medicine and director of the VCU Institute of Molecular Medicine.
With cancer the goal is to kill the cancer cells without killing the normal cells. That's really hard because cancer and regular cells are otherwise so similar in so many ways.
A microbubble approach is already in phase III clinical trials for heart disease. This approach could be used against many other types of cancer as well.
UTMD uses microscopic, gas-filled bubbles that provide great contrast against soft tissue when viewed using ultrasound equipment. The microbubbles can also be paired with complexes made to bind to specific areas of the body, allowing them to be targeted. In this study, a weakened adenovirus (a virus that is typically associated with respiratory infections) engineered to deliver the tumor-suppressing gene mda-7/IL-24 was joined to the microbubbles and delivered through the blood stream directly into the prostate. UTMD's ability to systematically target a disease site could revolutionize gene therapy.
A sufficiently complex gene therapy might some day execute a genetic program that will only give the order to kill a cell if the genetic program detects it is executing in a cancer cell.
Whereas in 2010 in the United States cancer treatment cost about $124.6 billion in 10 years cancer is projected to cost somewhere between $159 billion to $207 billion per year.
If cancer incidence and survival rates and costs remain stable and the U.S. population ages at the rate predicted by the U.S. Census Bureau, direct cancer care expenditures would reach $158 billion in 2020, the report said.
But will survival rates remain stable? When do cancer treatments finally start making a big impact? When do cancer treatments become less damaging to the rest of the body while also becoming much more able to kill cancer cells?
However, the researchers also did additional analyses to account for changes in cancer incidence and survival rates and for the likelihood that cancer care costs will increase as new technologies and treatments are developed. Assuming a 2 percent annual increase in medical costs in the initial and final phases of care – which would mirror recent trends – the projected 2020 costs increased to $173 billion. Estimating a 5 percent annual increase in these costs raised the projection to $207 billion. These figures do not include other types of costs, such as lost productivity, which add to the overall financial burden of cancer.
Lots more cancer survivors because of lots more cancer patients.
According to their prevalence estimates, there were 13.8 million cancer survivors alive in 2010, 58 percent of whom were age 65 or older. If cancer incidence and survival rates remain stable, the number of cancer survivors in 2020 will increase by 31 percent, to about 18.1 million. Because of the aging of the U.S. population, the researchers expect the largest increase in cancer survivors over the next 10 years to be among Americans age 65 and older.
Many technologies develop for decades before reaching critical mass in terms of their effects. Look at how the semiconductor technology advances made computers keep growing more powerful until desktop, laptop, and handheld computers became first possible and then widespread. Technologies follow S curves in uptake when they suddenly become powerful and useful enough to enable widespread effective use. I expect the same with anti-cancer biotechnologies. But it is hard to guess when cancer treatments will become highly effective for most cancers.
Is there a way to predict when biotechnologies such as microfluidic devices will enable development of highly selective and effective anti-cancer treatments?
Johnson & Johnson is teaming up with Massachusetts General Hospital to try to bring to market a microchip that can detect cancer at very low concentrations in the blood.
Researchers at Massachusetts General Hospital have already developed a prototype of a microchip that can detect tumor cells at extremely low levels in the bloodstream. The effort to be announced today intends to draw on the expertise of scientists familiar with how to bring such technologies to patients and doctors.
The hope is to lower costs below the current $500 per chip. A big cost reduction seems a reasonable expectation because small things like computer chips get cheaper every year. Biotechnology is increasingly following the pattern of the semiconductor computer industry with rapid cost reduction and greater power.
The prototype, developed by Mehmet Toner and collaborators at MGH, consists of a business-card-size silicon chip dotted with tens of thousands of microscopic posts. Each post is coated with a molecule that binds to a protein unique to cells from a specific type of tumor, such as breast, lung, or prostate cancer
Where I think this is going: Cheap home cancer tests as well has home tests for many other diseases. The ability to cheaply and frequently test for a large range of diseases will enable much earlier stage diagnosis and increase the odds of cures.
"The results of the study suggest a new way to approach cancer treatment," said Richard Barth Jr., MD, Chief of General Surgery at Dartmouth-Hitchcock Medical Center and a member of the Gastrointestinal Clinical Oncology Group at Dartmouth-Hitchcock Norris Cotton Cancer Center, who is the study's principal investigator. "Basically, we've worked out a way to use dendritic cells, which initiate immune responses, to induce an antitumor response."
So the cancer had already mutated the ability to metastatize and had created a secondary tumor in the liver big enough to identify and remove. In these cases the odds are very high the tumor has landed in other places and the removal from the liver just buys some time. But in those patients who had tumors removed from their livers and who produced an immune response to the vaccine most unexpectedly survived over 5 years.
In the study, Barth first operated on 26 patients to remove tumors that had spread from the colon to the liver. While some of these patients would be expected to be cured with surgery alone, most of them would eventually die from tiny metastases that were undetectable at the time the tumors were removed from the liver. The DC vaccine treatment was given one month after surgery. The results were that T-cell immune responses were induced against the patient's own tumor in more than 60% of the patients. The patients were followed for a minimum of 5.5 years.; Five years after their vaccine treatment, 63% of the patients who developed an immune response against their own tumor were alive and tumor-free. In contrast, just 18% of the patients who did not develop an immune response against their own tumor were alive and tumor-free.
Since they were followed for a minimum of 5.5 years these people were treated in 2004 and even earlier. So if this vaccine were widely available for the last 5 years lots more people would be alive. I wonder when the vaccine will become widely available. If it was up to me it would become immediately available. But I do not think like FDA bureaucrats.
What about the people who do not produce an immune response to the tumor is their immune system weakened by chemo or radiation? Or is their immune system too old or are they poorly nourished? Or does their immune system just lack the antibodies that could respond to the antigens? Or what?
He said DC vaccines have been a research interest at many institutions, and previous studies showed that DC vaccines could not reduce or eliminate measurable metastatic tumor deposits. "It turned out we were asking the T-cells to do too much," he commented. "The small number of T-cells that are generated by a vaccine can't destroy a large tumor. However, what they may be able to do is search out and destroy tumor cells that exist as only microscopic tumor deposits. Once we brought patients into a measurable tumor-free condition with surgery, the anti-tumor T-cells induced by the DC vaccine may help keep them that way."
INDIANAPOLIS – A potent anti-tumor gene introduced into mice with metastatic melanoma has resulted in permanent immune reconfiguration and produced a complete remission of their cancer, according to an article to be published in the December 2010 issue of the Journal of Clinical Investigation. The online version is now available.
The cloned gene came from a patient with melanoma and the gene amped up immune response to melanoma.
Indiana University School of Medicine researchers used a modified lentivirus to introduce a potent anti-melanoma T cell receptor gene into the hematopoietic stem cells of mice. Hematopoietic stem cells are the bone marrow cells that produce all blood and immune system cells.
The T cell gene, which recognizes a specific protein found on the surface of melanoma, was isolated and cloned from a patient with melanoma. The gene-modified stems cells were then transplanted back into hosts and found to eradicate metastatic melanoma for the lifetime of the mice.
A result like this will take years before it is tried on humans. But why? If you've been given a malignant melanoma diagnosis death sentence by a doctor why shouldn't you be allowed to get highly experimental gene therapies? That people with fatal diseases can't bypass the drug approval process and try anything that works on lab animals just seems immoral to me.
Stromal cells in tumors excrete a protein that tells the immune system not to attack cancer cells. A way to suppress that protein would open up tumors to immune attack.
Researchers at the University of Cambridge hope to revolutionise cancer therapy after discovering one of the reasons why many previous attempts to harness the immune system to treat cancerous tumours have failed.
New research, published today in the journal Science, reveals that a type of stromal cell found in many cancers which expresses fibroblast activation protein alpha (FAP), plays a major role in suppressing the immune response in cancerous tumours – thereby restricting the use of vaccines and other therapies which rely on the body's immune system to work. They have also found that if they destroy these cells in a tumour immune suppression is relieved, allowing the immune system to control the previously uncontrolled tumour.
Tumors need many mutations in order to grow. Mutations that allow them to suppress immune response probably are among the mutations that make cancers more deadly.
In transgenic mice wiping out the stromal cells that make FAP opened up the tumors to immune attack.
In order to determine if FAP expressing stromal cells contribute to the resistance of a tumour to vaccination, the researchers created a transgenic mouse model which allowed them to destroy cells which expressed FAP. When FAP-expressing cells were destroyed in tumours in mice with established Lewis lung carcinomas (of which only 2% of the tumour cells are FAP-expressing), the cancer began to rapidly 'die'. The Fearon lab now hopes to collaborate with scientists at the CRUK Cambridge Research Institute to evaluate the effects of depleting FAP-expressing cells in a mouse model that more closely resemble human cancer, and to examine FAP-expressing cells of human tumours.
Drugs that would suppress or block FAP might work to activate the immune system to wipe out cancers. During such a drug treatment the patient might also experience harm from auto-immune attacks on healthy cells. Well, as compared to death from terminal cancer a temporary auto-immune disease would probably be the lesser of two evils.
One of the biggest benefits from the continuing plunge in DNA testing costs is going to be earlier diagnosis of cancers. One DNA test under development for colon cancer detection will be usable at home.
David Ahlquist, M.D., professor of medicine and a consultant in gastroenterology at the Mayo Clinic in Rochester, said much of that low rate may be due to inconveniences associated with conventional approaches.
"There is definitely an incentive and legitimate justification to be designing a screening approach that is user friendly, affordable and has the ability to detect pre-cancers," said Ahlquist. "The noninvasive stool DNA test we have developed is simple for patients, involves no diet or medication restriction, no unpleasant bowel preparation, and no lost work time, as it can be done from home. Positive tests results would be followed up with colonoscopy."
Some might think "home stool DNA tester, how gross". But I'll tell you what's gross: watching an adult you've known and loved for years experiencing excruciating pain from cancer metastases throughout their bones while they lose so much weight that they shrink up to skin-and-bones worse than concentration camp survivors.
The test that Ahlquist and colleagues evaluated is under development by Exact Sciences, a molecular diagnostics company in Wisconsin.
The test, which is not yet approved by the FDA, is conducted using a stool sample and works by detecting tumor-specific DNA alterations in cells that are shed into the stool from pre-cancerous or cancerous lesions.
As Nicholas Wade reports, the Exact Sciences test is one of two colon cancer DNA tests headed to market. The second test would require a blood sample.
The other test looks in blood for changes in a single gene, called Septin 9, which is not in the Exact Sciences’ panel of four genes. The test has been developed by Epigenomics AG in Germany. Both tests would be less expensive than colonoscopy, and potentially more effective. Compliance with colonoscopy is low, since people don’t want to have one, and the overall cost per detection is high because most people are healthy, and even colonoscopy misses many tumors in the upper part of the intestine.
Click thru and read Wade's articles for the caveats. But note that whatever limitations these tests have today they are just the beginning.
You only get colonoscopy results when you go to the trouble, cost, and small but real risk of getting a colonoscopy. Whereas a home DNA test would cost much less and could be done much more often. The higher frequency of testing would in theory catch the cancer at a much earlier stage. Once the home DNA test turns up positive the person could go in for a colonoscopy to remove polyps or other growths.
Since some cancers develop literally over almost 2 decades early diagnosis opens up the potential of finding and removing cancers long before they become life threatening. Once home tests of blood and saliva for DNA (and likely for antigens) to detect cancer become cheap and widely available the challenge is going to be to find the early stage cancers. Early stage means they will be small. How to find them?
If the tests can narrow down the cancer source to a single organ then excising the cancerous tissue might not be continue to be necessary. Eventually we'll be able go in for new replacement organs. If a test could, for example, indicate presence of a pancreatic cancer 10 years before it will metastasize then in 2030 the solution might be to start growing a new one in a lab. Get the new one after 6 months or a year and toss out the old one.
Pancreatic cancer has long been viewed as a rapidly developing cancer because life expectancy from day of diagnosis is usually less than 3 years with 95% of those diagnosed dead within 5 years. But use of DNA sequencing technology has enabled researchers Christine Iacobuzio-Donahue, Bert Vogelstein, and evolutionary biologist Martin Nowak to determine that most pancreatic cancers almost 20 years to develop enough to kill their victims.
Pancreatic tumors are one of the most lethal cancers, with fewer than five percent of patients surviving five years after diagnosis. But a new study that peers deeply into the genetics of pancreatic cancer presents a bit of good news: an opportunity for early diagnosis. In contrast to earlier predictions, many pancreatic tumors are, in fact, slow growing, taking nearly 20 years to become lethal after the first genetic perturbations appear.
The great hope from this finding is that blood or stool tests will enable identification of cancer at a much earlier and treatable stage. Early detection might involve genetic testing. Or possibly the mutations cause differences in surface proteins that could be detected with an immune protein test.
Imagine getting extensive tests done to your blood and assorted secretions every few years to detect early stage cancers and other disease processes. Acting on the results seems very hard though. Suppose a blood test showed you to have early stage pancreatic cancer 10 years before you'd otherwise be diagnosed. Okay, how to find it? Sure, it is in your pancreas. But how to identify which part of the pancreas to remove? Lots of biopsies where each biopsy gets genetically tested? Would that work? Remember, the earlier the cancer gets detected the smaller it'll be. What are the odds of narrowing down its precise location 15 years before it will make you ill?
My guess is that very early stage pre-cancerous pancreatic cell mutations either won't be detectable via blood tests or they'll be too small to find. Another possibility: many more pre-cancers will be detected than actually go on to become cancers. The trick will be to only go in surgically to remove the intermediate stage cancers that are not yet metastatic but sufficiently mutated to pose such a high enough risk as to warrant treatment.
Working with Iacobuzio-Donahue, Vogelstein obtained samples of primary pancreatic tumors from seven autopsied patients, as well as metastatic lesions from their lungs, liver, and other organs. Their team sequenced the DNA of every gene in each metastatic tumor as well as in the primary tumor. These genetic read-outs provided data to compare the genetic mutations found in each patient’s metastatic lesions with the mutations found in the primary tumor.
This research was made possible by advances that lowered the cost of genetic sequencing. Future declines in genetic sequencing costs will enable even faster rates of discovery of genetic mutations which contribute to the development and spread of cancer.
Want to know a decade in advance that you are at high risk of future pancreatic cancer?
The technique showed that it took a surprisingly long time – 11.7 years on average – for a mature pancreatic tumor to form after the appearance of the first cancer-related mutation in a pancreatic cell. Another 6.8 years passed, on average, before the primary tumor sent out a metastatic lesion to another organ. From that point, another 2.7 years went by, on average, before the patient died. In total, more than 20 years elapsed between the appearance of the first mutated pancreatic cell and death.
“This time scale is similar to what we’ve previously seen in colorectal cancers,” says Vogelstein. “These tumors evolve over long periods --decades.”
I am reminded of the late cancer researcher Judah Folkman's observation that we've got many small cancers in our bodies that have not mutated enough to cause blood vessel growth (by mutations that increase angiogenesis compound secretion). So we have lots of cancers that are stuck in our organs at very small sizes (yes, you probably have cancer cells in you). The hard part of trying to remove cancers at that stage is finding them.
Another useful result from this research: each of the metastases is genetically distinct. This makes killing al the metastases hard. Each has its own unique resistances to different chemotherapeutic agents. But the earlier cancer gets detected the less genetically heterogeneous it will be.
"We have always known that pancreatic cancer is a particularly aggressive disease," says Dr Peter Campbell, from the Wellcome Trust Sanger Institute and first author on the paper. "This study illustrates why it is so challenging. Each metastasis is its own tumour, each evolving, each striving for dominance, each adapting to life outside the pancreas. When we treat cancer that has spread through the body, we're not just treating one tumour, we might be treating tens of genetically distinct tumours."
Cancerous intestinal polyps are pretty easy to discover with colonoscopy. Unfortunately the pancreas isn't as easy to inspect as the colon. But we need the ability to remove the pancreatic equivalents of colon polyps.
The Hopkins work, published in the October 28 issue of the journal Nature, suggests that it takes at least a decade for the first cancer-causing mutation that occurs in a cell in a pancreatic lesion to turn into a full-fledged cancer cell. At this point, the lesion is called "high-grade" and should be removed, much like polyps are removed from the colon.
After the first cancer cell appears, it takes an average of nearly seven years for that cell to turn into the billions that make up a cancerous tumor the size of a plum, after which at least one of the cells within the tumor has the potential and ability to spread to other organs. Patients die an average of two and a half years after this metastasis.
An experimental drug designed to block the effects of a genetic mutation often found in patients with malignant melanoma, a deadly cancer with few existing treatments, significantly shrank tumors in about 80 percent of those who carried the mutation.
Click thru and read all the details.
A small percentage of the patients experienced disappearance of tumours. But do not expect it at a doctor's office any time soon.
Further studies are needed before the drug can be approved by the FDA.
I find this infuriating. Once you've been given a death sentence diagnosis and have months to live why should you have to die without being able to try experimental treatments?
Stage IV metastatic variety of melanoma has a 5 year survival rate below 20% and even lower in some cases. Malignant melanoma diagnosis amounts to a check-out notice from the Life Hotel. Such check-out notices ought to entitle you to a "Get out of the FDA jail card" where you get to try experimental treatments.
Researchers at UCLA’s Jonsson Comprehensive Cancer Center created a large, well armed battalion of tumor-seeking immune system cells and watched, in real time using Positron Emission Tomography (PET), as the special forces traveled throughout the body to locate and attack dangerous melanomas.
But for now this sort of thing only gets done for those tricky lab mice who have done such a great job of convincing researchers into developing medical treatments for them first.
If I had terminal cancer and a large sum of money I'd hire medical researchers to do this to my own immune system.
The gene therapy work, done with melanomas grown in mice, employed a crippled HIV-like virus to serve as a vehicle to arm the lymphocytes with T cell receptors, which caused the lymphocytes to become specific killers of cancerous cells. A reporter gene, which glows “hot” during PET scanning, also was inserted into the cells so researchers could track the genetically engineered lymphocytes after they were injected into the blood stream, made their way to the lungs and lymph nodes and then specifically homed in on the tumors wherever they were located within the body.
“We’re trying to genetically engineer the immune system to become a cancer killer and then image how the immune system operates at the same time,” said Dr. Antoni Ribas, an associate professor of hematology/oncology, a researcher at UCLA’s Jonsson Comprehensive Cancer Center and the senior author of the study. “We knew this approach of arming the lymphocytes with T cell receptors showed significant anti-tumor activity based on studies in humans. Now, by tracking the immune system’s reaction to cancer and imaging it in real time, we can project how the same process that succeeded in mice might behave in people.”
The study is published July 12, 2010 in the early online edition of the journal Proceedings of the National Academy of Sciences.
I like the part in bold. Sure beats dying in a shriveled painful state of a horrible disease.
“The novelty of our work is that we were able to pack together the cancer specific T cell receptor and the PET reporter genes in a single vector and use it in mice with an intact immune system that closely resembles what we would see in real patients,” said Dr. Richard Koya, an assistant professor of surgical oncology at UCLA’s David Geffen School of Medicine and first author of the study. “We were also gladly surprised to see the targeted tumors literally melt away and disappear, underscoring the power of the combined approach of immune and gene therapy to control cancer.”
Time to do this in humans who have a few months to live. Maybe Chinese researchers will do it without waiting a long time to do more animal tests.
When loaded with an anticancer drug, a delivery system based on a novel material called nanosponge is three to five times more effective at reducing tumor growth than direct injection.
That is the conclusion of a paper published in the June 1 issue of the journal Cancer Research.
"Effective targeted drug delivery systems have been a dream for a long time now but it has been largely frustrated by the complex chemistry that is involved," says Eva Harth, assistant professor of chemistry at Vanderbilt, who developed the nanosponge delivery system. "We have taken a significant step toward overcoming these obstacles."
So far these nanosponges have only been tested in mice.
The nanosponges work in a manner similar to viruses in that they bind to surface antigens on target cells.
To visualize Harth's delivery system, imagine making tiny sponges that are about the size of a virus, filling them with a drug and attaching special chemical "linkers" that bond preferentially to a feature found only on the surface of tumor cells and then injecting them into the body. The tiny sponges circulate around the body until they encounter the surface of a tumor cell where they stick on the surface (or are sucked into the cell) and begin releasing their potent cargo in a controllable and predictable fashion.
To make this delivery vehicle work well researchers must come up with antigens on the surface of each instance of cancer that are not found much in the rest of the body. Does anyone know whether cancer cell outer surfaces can be expected to contain unique antigens that are distinct from those found on the surfaces of non-cancer cells? Is this even a question that has a known answer yet for most types of cancer?
PASADENA, Calif.—A California Institute of Technology (Caltech)-led team of researchers and clinicians has published the first proof that a targeted nanoparticle—used as an experimental therapeutic and injected directly into a patient's bloodstream—can traffic into tumors, deliver double-stranded small interfering RNAs (siRNAs), and turn off an important cancer gene using a mechanism known as RNA interference (RNAi). Moreover, the team provided the first demonstration that this new type of therapy, infused into the bloodstream, can make its way to human tumors in a dose-dependent fashion—i.e., a higher number of nanoparticles sent into the body leads to a higher number of nanoparticles in the tumor cells.
These results, published in the March 21 advance online edition of the journal Nature, demonstrate the feasibility of using both nanoparticles and RNAi-based therapeutics in patients, and open the door for future "game-changing" therapeutics that attack cancer and other diseases at the genetic level, says Mark Davis, the Warren and Katharine Schlinger Professor of Chemical Engineering at Caltech, and the research team's leader.
Will most cancer be cured by more precise delivery of toxins into cancer cells? Or will genetic reprogramming of cancer cells with gene therapy or regulatory RNAs ( as above) do the trick? I like the reprogramming approach because it is like a software update. Upload a software patch to tell those cancer cells to stop dividing.
For a long time nanotechnology was one of those technologies that lay only in our future. It is starting to show up in our present. Cornell researchers have attached antibodies to nanoparticles to attack colorectal cancer cells.
ITHACA, N.Y. - Another weapon in the arsenal against cancer: Nanoparticles that identify, target and kill specific cancer cells while leaving healthy cells alone.
Led by Carl Batt, the Liberty Hyde Bailey Professor of Food Science, the researchers synthesized nanoparticles – shaped something like a dumbbell – made of gold sandwiched between two pieces of iron oxide. They then attached antibodies, which target a molecule found only in colorectal cancer cells, to the particles. Once bound, the nanoparticles are engulfed by the cancer cells.
To kill the cells, the researchers use a near-infrared laser, which is a wavelength that doesn't harm normal tissue at the levels used, but the radiation is absorbed by the gold in the nanoparticles. This causes the cancer cells to heat up and die.
"This is a so-called 'smart' therapy," Batt said. "To be a smart therapy, it should be targeted, and it should have some ability to be activated only when it's there and then kills just the cancer cells."
One can imagine a variety of ways to activate toxins once those toxins have entered cancer cells. The trick is preferentially getting the toxins into cancer cells so that other cells in the body do not get poisoned by the poison payload. To just come up with antibodies that will target all the cancer in a body is a major challenge.
I am wondering whether cancer will ultimately be stopped by precisely delivered poisons or by pieces of RNA delivered into cancer cells to suppress and activate selected genes in the DNA. It is like the difference between bombs and software. Blow up the cells up or regain control over them?
Scientists have sequenced the genomes of two tumors from the same breast cancer patient--a primary tumor and a metastatic tumor that occurred nine years later--illuminating some of the genetic changes that trigger the progression of cancer. The initial findings suggest that both primary cancers and the process of metastasis--the spread of cancer cells--are more complicated and more variable than expected, which means that successful cancer treatment might ultimately require a combination of drugs targeted to different mutations.
The project is also a testament to how easy it has become to sequence a human genome. The researchers, from the British Columbia Cancer Agency, in Vancouver, now plan to sequence the tumor genomes of more than 250 additional patients over the next year. "We are sequencing dozens of tumors a week now," says Samuel Aparicio, the scientist who led the study.
The decline in DNA sequencing costs from hundreds of millions of dollars per person to several thousands of dollars has suddenly made many types of scientific investigation possible. By doing sequencing of tumors at different stages in large numbers of patients scientists will develop a much better picture of which mutations occur in people to cause their cancers become more malignant and deadly. This will lead to treatments aimed at the most deadly mutations.
The amount of data involved in this sort of research is enormous. Each sequencing turns up data for a few billion DNA letters. A cancer patient could get sequencing done at each stage of their cancer. With about 1.6 million people in the United States alone suffering from cancer the total amount of complete genome sequencing that will get done just for cancer patients will equal at least that number per year in order to track existing cancers thru stages of development.
A new study suggests that delivering small RNAs, known as microRNAs, to cancer cells could help to stop the disease in its tracks. microRNAs control gene expression and are commonly lost in cancerous tumors. Researchers have shown that replacement of a single microRNA in mice with an extremely aggressive form of liver cancer can be enough to halt their disease, according to a report in the June 12 issue of the journal Cell, a Cell Press publication.
Cancer amounts of cells that have damaged programs. Their information state is incorrect. MicroRNAs work naturally in cells to regulate gene expression. Using microRNAs to change how the genetic program of a cell executes amounts to attacking cancer on the level where it goes wrong in the first place. This is how I expect cancer will eventually be cured.
The microRNA was packed into viruses and those viruses carried the microRNA into cells. That can be problematic for a few reasons including immune attacks against viruses. But the viruses worked well in this instance..
They delivered the microRNA to the mice using a virus that has been applied in other forms of gene therapy. That so-called adeno-associated virus (AAV) is particularly good at targeting new genetic material to the liver.
"Mice given the control virus showed no change in the growth rate of their tumors and within three weeks, the cancer had taken over," said Joshua Mendell of Johns Hopkins University School of Medicine. "When we gave them the microRNA-carrying virus, some animals showed essentially complete regression of their tumors." In other cases, he said, the tumors were much smaller and far fewer.
Mendell said his team, which included his father Jerry Mendell at The Research Institute at Nationwide Children's Hospital, was hopeful the strategy would work based on previous evidence. Nonetheless, he added, "it is always surprising to see results this striking."
One problem with curing cancer is that large numbers of of cells are usually involved by the time of diagnosis. Viruses would need to enter just about every cancer cell in order to totally eradicate the cancer. I'm therefore surprised this treatment worked as well as it did.
The microRNA was highly selective in only changing cancer cells.
They were also amazed by how specifically the microRNA affected cancer cells, while leaving normal cells unscathed. "We found that the tumor cells are exquisitely sensitive [to microRNA replacement]--they not only stopped proliferating, but they actually died," he said. Meanwhile, the mice showed no evidence of any damage to their normal liver tissue.
Cancer is a major problem for those of us who want to reverse aging with rejuvenation therapies. Even young people die from cancer. Youthfulness is not a guaranteed protector against cancer. Rejuvenation by itself is not enough to protect us against cancer. We also need the ability to wipe out cancer cells and do so with little collateral damage. Therapies based on microRNAs might provide us with this capability.
Our genome is coded as DNA. But it gets translated into RNA which serves a variety of roles including as regulatory molecules. Naturally occurring silencing RNAs (siRNAs) are short RNA genetic sequences that bind to other RNAs to suppress genes. Cancer researchers are looking at using siRNAs to try to regulate cancer cells to tell them to stop growing and even to commit cell suicide (apoptosis). Some UCSD researchers are making progress on an siRNA anti-cancer drug delivery mechanism.
In technology that promises to one day allow drug delivery to be tailored to an individual patient and a particular cancer tumor, researchers at the University of California, San Diego School of Medicine, have developed an efficient system for delivering siRNA into primary cells. The work will be published in the May 17 in the advance on-line edition of Nature Biotechnology.
"RNAi has an unbelievable potential to manage cancer and treat it," said Steven Dowdy, PhD, Howard Hughes Medical Institute Investigator and professor of cellular and molecular medicine at UC San Diego School of Medicine. "While there's still a long way to go, we have successfully developed a technology that allows for siRNA drug delivery into the entire population of cells, both primary and tumor-causing, without being toxic to the cells."
RNA interference amounts to attacking cancers at the level of cellular regulation with the siRNAs almost like software patches. Since regulatory mechanisms gone awry cause cancer in the first place the siRNA approach attacks cancer on the level where things go wrong and cells become cancerous. The siRNAs are smaller than DNA delivered as gene therapy. But they are still quite powerful.
Cancers mutate at a fast rate and therefore develop resistance to anti-cancer drugs. The cells in a tumor are not all genetically identical. So natural selection operates on cancer cells in the presence of chemotherapy drugs. Some survive and develop mutations that reduce their vulnerability to chemo and other anti-cancer therapies. But this RNAi approach can be very rapidly adjusted to deal with cancer mutations.
These RNAi methods can be continually tweaked to combat new mutations – a way to overcome a major problem associated with current cancer therapies. "Such therapies can't be used a second time if a cancer tumor returns, because the tumor has mutated the target gene to avoid the drug binding," said Dowdy. "But since the synthetic siRNA is designed to bind to a single mutation and only that mutation on the genome, it can be easily and rapidly changed while maintaining the delivery system – the PTD-DRBD fusion protein."
We need fast and cheap DNA sequencing and testing to allow rapid retargeting of siRNAs against cancer. This approach turns the war against cancer into an information war. At that level we can win.
An informative article in the New York Times describes the rather slow progress of attempts to cure cancer.
Cancer has always been an expensive priority. Since the war on cancer began, the National Cancer Institute, the federal government’s main cancer research entity, with 4,000 employees, has alone spent $105 billion.
If you think $105 billion sounds like a lot then look at this US GAO 2008 FY budget document. You can find multiple departments that each in a single year burn thru several times what the US government has spent in total to cure cancer. $105 billion is chump change for solving a problem that is, absent a cure, going to extremely painfully kill a large percentage of those reading this. To put it another way, its a little over $300 per American citizen. The costs of one year's lost productivity alone exceeds the total amount spent researching to find a cure. I'm digressing. But there's a point: We should try much harder to develop curative treatments for cancer.
After decades of new treatments the death rate from cancer hasn't declined much.
Yet the death rate for cancer, adjusted for the size and age of the population, dropped only 5 percent from 1950 to 2005. In contrast, the death rate for heart disease dropped 64 percent in that time, and for flu and pneumonia, it fell 58 percent.
It is a lot easier thru diet to cut heart disease risk than to cut cancer risk. It is also a lot easier to use drugs to alter metabolism to lower heart disease and other cardiovascular disease risks. Statins and blood pressure drugs will cut your heart disease risks. Also, emergency treatments for heart attack can reduce fatality rates long enough that drugs and diet can cut the risk of recurrence. Even still, you can chance your diet in many useful ways to cut your cancer risks. Do what you can to cut your risks. You might just avoid cancer long enough to still be around when cures are developed.
Think great progress has been made against cancer? Once a cancer mutates to enable metastasis the odds of survival become very low.
With breast cancer, for example, only 20 percent with metastatic disease — cancer that has spread outside the breast, like to bones, brain, lungs or liver — live five years or more, barely changed since the war on cancer began.
With colorectal cancer, only 10 percent with metastatic disease survive five years. That number, too, has hardly changed over the past four decades. The number has long been about 30 percent for metastatic prostate cancer, and in the single digits for lung cancer.
This illustrates the value of early detection. The earlier the detection the greater the chance that the cancer hasn't spread to more locations - especially not to inoperable locations. More powerful testing techniques might lead to more earlier detection. But I suspect that to really make early detection the means to cure more cancers will require development of assay technologies that work at home. To reliably detect cancers before metastasis but after they've has gotten big enough to create a clear biochemical signature in blood, saliva, or other secretions might require very frequent testing.
The article quotes a medical researcher who argues that the funding for treatment development is too conservative and aimed at developing treatments that will yield small increases in survival at lower risk of experimental failure. We need funding for higher risk but potentially much higher benefit treatments.
The problem with cancer is that it is your own cells going wild. It is very very hard to selectively kill all cancer cells while at the same time killing few of your own normal cells. To achieve such a high degree of selectivity requires an enormous amount of understanding of how cancer cell metabolism differs from normal cell metabolism. That, in turn, requires experimental tools far more powerful than what cancer researchers have had to work with for the vast bulk of the time they've been doing the research. Even today scientists still do not have a sufficiently detailed understanding of cellular regulation to know all the mechanisms where genetic mutation and epigenetic state change can turn cells cancerous, capable of extended growth, and metastatic.
New research from South Dakota State University offers evidence that including flax in the diet may help prevent colorectal tumors or keep tumors from growing as quickly when they do form.
Distinguished professor Chandradhar Dwivedi, head of SDSU’s Department of Pharmaceutical Sciences, directed the study by departmental graduate student researchers Ajay Bommareddy, Xiaoying Zhang and professional doctor of pharmacy student Dustin Schrader.
“The study was conducted in a special strain of mice that develop spontaneous intestinal tumors due to mutation in a gene,” Dwivedi said.
“This model is developed to investigate the effects of cancer preventive agents on genetically predisposed individuals,” he said.
“Results indicated that mice on diets supplemented with flaxseed meal and flaxseed oil had, on average, 45 percent fewer tumors in the small intestine and the colon compared to the control group.”
Maybe the lignan compounds or the alpha-linolenic acid in flax cut the cancer risks
Picture a drug based on RNA as a mini computer program aimed at running in our cells rather than in a silicon computer. Such a drug in theory could carry out much more complex behaviors than conventional simpler chemical compounds. Stanford researchers are working on RNA-based drugs that would only turn on in cancer cells.
Current treatments for diseases like cancer typically destroy nasty malignant cells, while also hammering the healthy ones. Using new advances in synthetic biology, researchers are designing molecules intelligent enough to recognize diseased cells, leaving the healthy cells alone.
"We basically design molecules that actually go into the cell and do an analysis of the cellular state before delivering the therapeutic punch," said Christina Smolke, assistant professor of bioengineering who joined Stanford University in January.
This is the sort of approach we need to wipe out cancer. The current chemo drugs are nowhere near specific enough in the cells they target. The whole body ends up getting damaged. Also, the rates of failure for chemo are very high for many types of cancer.
The trick is to activate only in the presence of biomarker materials that are characteristic of cancer cells. That's a tough job because human cancer cells are human cells. Coming up with suitable biomarkers and ways to make RNA react to them is not easy.
"When you look at a diseased cell (e.g. a cancer cell) and compare it to a normal cell, you can identify biomarkers—changes in the abundance of proteins or other biomolecule levels—in the diseased cell," Smolke said. Her research team has designed molecules that trigger cell death only in the presence of such markers. "A lot of the trick with developing effective therapeutics is the ability to target and localize the therapeutic effect, while minimizing nonspecific side effects," she said.
Smolke will present the latest applications of her lab's work at the American Association for the Advancement of Science (AAAS) meeting in Chicago on Friday, Feb. 13.
These designer molecules are created through RNA-based technologies that Smolke's lab developed at the California Institute of Technology. A recent example of these systems, developed with postdoctoral researcher Maung Nyan Win (who joined Smolke in her move to Stanford), was described in a paper published in the Oct. 17, 2008, issue of Science.
"We do our design on the computer and pick out sequences that are predicted to behave the way we like," Smolke said. When researchers generate these sequences inside the operating system of a cell, they reprogram the cell and change its function. "Building these molecules out of RNA gives us a very programmable and therefore powerful design substrate," she said.
The ability to selectively kill all cancer cells in the body would not only put an end to cancer as a killer but also open up the door to a lot more therapies for other diseases. Hormone replacement therapies that increase the risk of cancer would no longer pose that problem for their use. So we could jack up our aging metabolisms with hormones and pay less of a price for doing so.
Using a sort of hacking approach to drug activation to only turn toxic drugs on in cancer cells is an obvious idea and other groups are working on it. See my 2004 post DNA Nanomachine Computers Against Cancer.
Scientists seeking to harness the power of the immune system to eradicate brain tumors face two major hurdles: recruiting key immune cells called dendritic cells into areas of the brain where they are not naturally found and helping them recognize tumor cells as targets for attack.
Researchers at Cedars-Sinai Medical Center, however, have identified a sequence of molecular events that accomplish both objectives. Their findings, based on laboratory and animal studies, appear in the Jan. 13 issue of PLoS Medicine, an open-access online journal of the Public Library of Science.
The Cedars-Sinai team discovered that a protein – HMGB1 – released from dying tumor cells activates dendritic cells and stimulates a strong and effective anti-tumor immune response. HMGB1 does so by binding to an inflammatory receptor called toll-like receptor 2, or TLR2, found on the surface of dendritic cells.
Here is part of the abstract of the research paper. Click thru to read the full paper.The researchers delivered gene therapy into the tumor mass and provoked an immune response.
Using a combined immunotherapy/conditional cytotoxic approach that utilizes adenoviral vectors (Ad) expressing Fms-like tyrosine kinase 3 ligand (Flt3L) and thymidine kinase (TK) delivered into the tumor mass, we demonstrated that CD4+ and CD8+ T cells were required for tumor regression and immunological memory. Increased numbers of bone marrow-derived, tumor-infiltrating myeloid DCs (mDCs) were observed in response to the therapy. Infiltration of mDCs into the GBM, clonal expansion of antitumor T cells, and induction of an effective anti-GBM immune response were TLR2 dependent.
But can the gene therapy get delivered with sufficient specificity for cancer cells that non-cancer cell loss is minimized?
Brain cancer is especially challenging because we can't afford to cut out large amounts of brain tissue in order to get the tumor. We need to find ways to very very selectively target just the cancer cells. That is especially true for brain tumors.
“New blood” can revitalize a company or a sports team. Recent research by Tel Aviv University finds that young blood does a body good as well, especially when it comes to fighting cancer.
The TAU researchers, led by Prof. Shamgar Ben-Eliyahu from the Department of Psychology’s Neuroimmunology Research Unit, discovered that a transfusion of “young” blood — blood which has been stored for less than 9 days — increased the odds of survival in animals challenged with two types of cancer. This finding, reported in the journal Anesthesiology, may solve an age-old mystery as to why some blood transfusions during cancer-related surgeries may lead to an increased recurrence of cancer and others do not.
“There is anecdotal evidence pointing to the fact that some surgeons really prefer to use younger blood units. They insist on it. Our research shows their reasoning might be sound,” says Prof. Ben-Eliyahu, explaining that the oldest blood in a blood bank usually sits on the shelf anywhere from 40 to 42 days before it expires.
Using an animal model, the researchers conducted tests on rats with leukemia and breast cancer. The odds of surviving the cancer, they found, were only compromised if the transfusion blood had been stored for nine or more days.
This result is not surprising. A group at Wake Forest University discovered that some mice have immune systems that are very effective against cancer and that group later discovered that rare people have extreme anti-cancer immune systems and that immune systems decline in their ability to attack cancer cells as we age. Blood that has not been stored as long probably is more capable for immune response.
I think the Wake Forest work demonstrates that not only should doctors use fresh blood with cancer patients but that they should use blood from younger donors and especially from donors which assays show to have especially effective immune responses against cancer.
The future development of immune system rejuvenation therapies will cut the incidence of cancer. Also, those rare people who have especially anti-cancer immune systems probably have genetic sequences for antibodies or perhaps for other parts of the immune system that make them fight cancer especially well. The eventual discovery of what makes their immune systems more effective will lead us toward the development of gene therapies or cell therapies to allow us to rev up our immune systems to protect against cancer.
In a PNAS paper some U Rochester researchers report they've discovered a modified gene which expresses itself 5 times more in cancer cells than in regular cells.
Vera Gorbunova, assistant professor of biology at the University of Rochester, and her team, Andrei Seluanov, assistant professor of biology, and graduate student Christopher Hine, were investigating Rad51, a protein that is expressed at about five times higher level in cancer cells than in healthy cells, when they stumbled on something very unexpected.
Think of DNA as software. We need software that acts like a killer virus in cancer cells but which doesn't do anything harmful in regular cells. The ability to deliver a piece of software into a cell that can execute in a way that only kills cancer cells would put curing cancer within reach. This discovery is a useful step toward that capability.
"We stripped off some of the Rad51 gene and replaced it with a marker protein DNA to see why Rad51 was five times more abundant in cancer cells," says Gorbunova. "We wanted to see if there was any way we could boost that difference and create a really useful cancer-targeting tool. We couldn't believe it when we saw the cancer cells expressing the engineered Rad51 around a thousand times more."
When Gorbunova first saw the huge discrepancy, she thought one of her graduate students had fumbled the lab test. Further tests showed that the altered Rad51 was expressed in some cancer cells as much as 12,500 times as often as healthy cells, says Gorbunova. Such a large discrepancy means scientists should be able to use it to create versions of Rad51 that carry a "toxic bomb," which only the cancer cells will trigger.
Rad51 is normally involved in DNA repair, which explains why it's more often expressed in cancer cells. Cancer cells reproduce at accelerated rates, often "not stopping to fix their DNA when they should," says Gorbunova. In these cancer cells, Rad51 is working overtime to repair all the damage, so it's not surprising that it is expressed more often.
Gorbunova believes that when she stripped out part of the Rad51-coding gene, she also stripped out some regulatory elements, which control the production of the protein. Without these elements, healthy cells ignore the gene and do not make the protein. However, these changes have opposite the effect on cancer cells, causing elevated, uncontrolled protein production.
Given a gene that will get turned on much more in cancer cells it becomes possible to tack something toxic onto it to do far more damage in cancer cells than in normal cells.
Gobunova and her team have already fused a variant of diphtheria toxin into the Rad51 gene as a "toxic bomb" and tested it on a variety of cancer cell types, including breast cancer, fibrosarcoma, and cervical cancer cells. The results look very promising, she says.
To make a gene therapy against cancer capable of a cure we would need a way to deliver gene therapy into almost all cells or at least almost all cells in an organ or almost all cells of some type. Otherwise a few cancer cells will escape and continue replicating.
Most cancers kill because they metastasize by traveling in the bloodstream, landing in other parts of the body, and then growing in each of these other locations. If cancer cells could be captured and killed in the bloodstream the chances of dying from cancer would go down substantially. Well, a Cornell University researcher has developed an implantable microtube that can capture cancer cells from the bloodstream and instruct them to die.
In a new tactic in the fight against cancer, Cornell researcher Michael King has developed what he calls a lethal "lint brush" for the blood -- a tiny, implantable device that captures and kills cancer cells in the bloodstream before they spread through the body.
Humans in the future are going to walk around with assorted biomedical implants. Sensors, cancer cell catchers, little drug reservoirs, and little chemical factories will all work to keep us healthy and control disease...
In research conducted at the University of Rochester and to be published in an upcoming issue of the journal Biotechnology and Bioengineering, King showed that two naturally occurring proteins can work together to attract and kill as many as 30 percent of tumor cells in the bloodstream -- without harming healthy cells.
King's approach uses a tiny tubelike device coated with the proteins that could hypothetically be implanted in a peripheral blood vessel to filter out and destroy free-flowing cancer cells in the bloodstream.
A cancer capturing microtube could also serve to detect cancer at early stages. For example, if the microtube started capturing a lot of cells that seem cancerous the microtube could change an attached bar code reader to a configuration that would signal "cancer" the next time it was read.
To capture the tumor cells in the blood, King used selectin molecules -- proteins that move to the surface of blood vessels in response to infection or injury. Selectin molecules normally recruit white blood cells (leukocytes) which "roll" along their surfaces and create an inflammatory response -- but they also attract cancer cells, which can mimic the adhesion and rolling process.
Once bound to selectin the cancer cells get exposed to the protein TRAIL (Tumor Necrosis Factor Related Apoptosis-Inducing Ligand) which connects to receptors on the cancer cells and send a signal for the cancer cells to die. One can imagine that some cancer cells will have genetic mutations that will cause them to ignore the suicide signal. So maybe this technique will need further enhancement to provide additional ways to cause the cancer cells to die.
King sees the device as years away from human use. I wonder if in the long run the tube will be replaced with genetically engineered cells that specialize in creating surfaces that catch cancer cells.
A new treatment strategy using molecular “smart bombs” to target metastasis with anti-cancer drugs leads to good results using significantly lower doses of toxic chemotherapy, with less collateral damage to surrounding tissue, according to a collaborative team of researchers at the University of California, San Diego. By designing a “nanoparticle” drug delivery system, the UC San Diego team, led by Moores UCSD Cancer Center Director of Translational Research David Cheresh, Ph.D., has identified a way to target chemotherapy to achieve a profound impact on metastasis in pancreatic and kidney cancer in mice.
In a study to be published online the week of July 7 in advance of publication in the Proceedings of the National Academy of Sciences (PNAS), Cheresh, professor and vice chair of pathology, and members of his team report that the nanoparticle carrying a payload of chemotherapy homes in on a protein marker called integrin ανβ3 – found on the surface of certain tumor blood vessels where it is associated with development of new blood vessels and malignant tumor growth.
The team found that the nanoparticle/drug combination didn't have much impact on primary tumors, but stopped pancreatic and kidney cancers from metastasizing throughout the bodies of mice. They showed that a greatly reduced dosage of chemotherapy can achieve the desired effect because the drug selectively targets the specific blood vessels that feed the cancerous lesion and kills the lesion without destroying surrounding tissue. The destruction of healthy tissue is a side-effect when chemotherapy is administered systemically, flooding the body with cancer-killing toxins.
“We were able to establish the desired anti-cancer effect while delivering the drug at levels 15 times below what is needed when the drug is used systemically,” said Cheresh. “Even more interesting is that the metastatic lesions were more sensitive to this therapy than the primary tumor.”
The problem with cancer cells is that they look too much like regular cells. We need much fancier nanoparticles that can enter cells and do complex checks to determine which cells are cancer cells. When a positive match is made for a cancer cell only then should chemotherapy molecules be released into a cell. I expect we'll get to that level of sophistication in the 2010s .
Massachusetts General Hospital (MGH) investigators have shown that an MGH-developed, microchip-based device that detects and analyzes tumor cells in the bloodstream can be used to determine the genetic signature of lung tumors, allowing identification of those appropriate for targeted treatment and monitoring genetic changes that occur during therapy. A pilot study of the device called the CTC-chip will appear in the July 24 New England Journal of Medicine and is receiving early online release.
“The CTC-chip opens up a whole new field of studying tumors in real time,” says Daniel Haber, MD, PhD, director of the MGH Cancer Center and the study’s senior author. “When the device is ready for larger clinical trials, it should give us new options for measuring treatment response, defining prognostic and predictive measures, and studying the biology of blood-borne metastasis, which is the primary method by which cancer spreads and becomes lethal.”
One can imagine a day when these sensors become cheap enough for routine blood testing for early diagnosis of cancer. Further out, implantable sensors could constantly watch for cancer cells and report to your cell phone when cancer is detected. "This text message is to inform you that you have very early stage liver cancer and should seek immediate treatment for a 99.99% chance of a cure."
Chips are the future of biotechnology. Smaller and more complex and powerful devices will slay many diseases.
The chip's ability to detect which drug resistance mutations each patient has can be used to guide choice of therapy.
Circulating tumor cells (CTCs) were identified in all cancer patients. Also, the chip identified which patients had genetic mutations in their tumors that made them resistant to certain forms of anti-cancer therapy.
The CTC-chip was used to analyze blood samples from 27 patients – 23 who had EGFR mutations and 4 who did not – and CTCs were identified in samples from all patients. Genetic analysis of CTCs from mutation-positive tumors detected those mutations 92 percent of the time. In addition to the primary mutation that leads to initial tumor development and TKI sensitivity, the CTC-chip also detected a secondary mutation associated with treatment resistance in some participants, including those whose tumors originally responded to treatment but later resumed growing.
The chip detected changes in concentrations of tumor cells. The chip will be able to detect a surge in cancer growth faster than X rays and with less harm and cost.
These visits were not timed for the purpose of the study, but Dr. Haber's group noted that in one case circulating tumor cell numbers dropped 50% within a week of staring therapy and continued to decline for three months.
Clinical progression was associated with an increase in the number of circulating tumor cells.
The researchers also reported "close concordance" between radiographic assessment of tumor volume and changes in the number of circulating tumor cells in patients followed throughout their course of therapy.
What I wonder: Will we ever get treated by something like a kidney dialysis machine but where the machine removes circulating cancer cells. One can imagine that upon diagnosis a patient could get hospitalized, hooked to a cancer cell catching machine, and then scheduled for surgery. During surgery the machine could continue to catch cancer cells that spill out into the blood as the surgeons cut into the tumor. Then the patient could remain on the machine for a few days after the surgery with the machine reporting the number of cancer cells getting caught per hour. If the count does not go down to 0 then the surgeons need to go looking for another pocket of cancer that they missed.
Chronic inflammation of the intestine or stomach can damage DNA, increasing the risk of cancer, MIT scientists have confirmed.
The researchers published evidence of the long-suspected link in the June 2 online issue of the Journal of Clinical Investigation (JCI).
In two studies, the researchers found that chronic inflammation accelerated tumor formation in mice lacking the ability to repair DNA damage.
"It's something that was expected but it was never formally proven," said Lisiane Meira, research scientist in MIT's Center for Environmental Health Sciences (CEHS) and lead author of the paper.
The results of this work suggest that people with decreased ability to repair DNA damage might be more susceptible to developing cancer associated with chronic inflammation such as ulcerative colitis, Meira said.
Inflammation caused by infectious agents such as Helicobacter pylori and Hepatitis C is known to increase the risk of stomach and liver cancers, respectively. Researchers have long known that inflammation produces cytokines (immune response chemicals that encourage cell proliferation and suppress cell death), which can lead to cancer.
In addition, it was suspected that another effect of the inflammation pathway could also induce cancer. During the inflammatory response to infection, immune cells such as macrophages and neutrophils release reactive oxygen and nitrogen species that can damage DNA.
The known cancer risk from Helicobacter pylori suggests that screening for Helicobacter pylori infection followed by treatment could cut the rate of stomach cancer. Helicobacter pylori is a quite curable infection. Some people find they have it when diagnosed with an ulcer. But others live without without knowing its presence in the stomach is upping their risk of stomach cancer. I've actually thought of getting tested for Helicobacter pylori but have never got off my butt to go ask a doctor for the test.
You can cut your risk of chronic inflammation by getting plenty of omega 3 fatty acids, vitamin D, a Mediterranean diet, and plenty of exercise. Of course do not smoke or otherwise expose yourself to toxins.
HOUSTON - A gene therapy invented at The University of Texas M. D. Anderson Cancer Center is the first to succeed in a U.S. phase III clinical trial for cancer, as announced today at the American Society of Gene Therapy annual meeting in Boston.
Introgen Therapeutics, Inc., reported results of its phase III trial of Advexin(r), a modified adenovirus that expresses the tumor-suppressing gene p53, for end-stage head and neck cancer.
"Cells become cancerous because p53 no longer functions. Restoring p53 works unlike any current cancer treatment because it treats the cancer genome," said Jack Roth, M.D., professor in M. D. Anderson's Department of Thoracic & Cardiovascular Surgery, who invented the drug and co-founded Introgen. He remains a shareholder and paid consultant to Introgen, and the University of Texas System is also a shareholder in Introgen.
The p53 gene is inactivated in many types of cancer. Its normal role is to halt the division of a defective cell and then force the cell to kill itself.
But the benefit is pretty small. Average life expectancy was still only 7.2 months.
The trial showed that p53 expression in the patient's tumor before treatment is a reliable biomarker for how to treat head and neck cancer. Patients with a favorable p53 profile who received Advexin(r) had a median survival of 7.2 months, compared with 2.7 months for those whose tumor expressed high levels of mutant p53 before treatment. Patients with this unfavorable profile were better off taking the chemotherapy drug methotrexate, resulting in median survival of 5.9 months.
A measly 7.2 months counts as an improvement. Geez.
Just when will cancer cures become easy to do? 10 years? 20 years? Progress still seems excruciatingly slow.
COLUMBUS, Ohio – Tumors require a blood supply to grow, but how they acquire their network of blood vessels is poorly understood. A new study here shows that tumor blood vessels can develop from precancerous stem cells, a recently discovered type of cell that can either remain benign or become malignant.
Researchers say the findings provide new information about how tumors develop blood vessels, and why new drugs designed to block tumor blood-vessel growth are often less effective than expected.
The study by scientists at the Ohio State University Comprehensive Cancer Center and Department of Pathology is to be published Feb. 20 in the journal PLoS ONE.
“These findings suggest that tumor blood vessels are derived mainly from tumor cells, with a smaller number coming from normal blood-vessel cells,” says principal investigator Jian-Xin Gao, assistant professor of pathology.
“This may explain why many anti-angiogenic drugs fail to block tumor growth.”
The recently deceased pioneer of anti-angiogenesis research against cancer, Harvard Medical School's Judah Folkman MD, in lectures showed stained slides of thyroids and other organs showing as people get older they have lots of small cancers in their bodies (yes, you have lots of small cancers in your body). These little cancers are all stuck at a stage where they can't grow any larger due to lack of ability to stimulate blood vessel growth. So they are stopped by lack of nutrients.
Maybe some cancers get past that obstacle by having some of their cells mutate into blood vessel generating cells. Or maybe mutations in blood vessel cells happen near existing mutated cancer cells. Then these two cell types basically team up to kill you. Either way, this report is bad news.
You can read the full research paper available in open access: Precancerous Stem Cells Can Serve As Tumor Vasculogenic Progenitors.
A new gene therapy approach that attracts and “trains” immune system cells to destroy deadly brain cancer cells also provides long-term immunity, produces no significant adverse effects and -- in the process of destroying the tumor -- promotes the return of normal brain function and behavioral skills, according to a study conducted by researchers at Cedars-Sinai Medical Center’s Board of Governors Gene Therapeutics Research Institute.
The study was conducted in a recently developed laboratory rat model of glioblastoma multiforme (GBM) that closely simulates outcomes in humans and supports the translation of this procedure to human clinical trials later this year. Results of the study are described in the Feb. 19 issue of Molecular Therapy, the journal of the American Society for Gene Therapy.
Gene therapy to train immune systems to attack cancers seems one of the most promising approaches against cancer.
New Haven, Conn. — Researchers at Yale School of Medicine have developed a blood test with enough sensitivity and specificity to detect early stage ovarian cancer with 99 percent accuracy.
Results of this new study are published in the February 15 issue of the journal Clinical Cancer Research. The results build on work done by the same Yale group in 2005 showing 95 percent effectiveness of a blood test using four proteins.
So what became of the blood test that is 95% efficient? What would it cost for mass usage? How frequent would a test like this need to be delivered? Once a year? Once a quarter? How quickly does the cancer go from being detectable to having metastasized? Also, how hard is it to find and remove only the still very small early stage cancer and not the whole organ?
“The ability to recognize almost 100 percent of new tumors will have a major impact on the high death rates of this cancer,” said lead author Gil Mor, M.D., associate professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale. “We hope this test will become the standard of care for women having routine examinations.”
Epithelial ovarian cancer is the leading cause of gynecologic cancer deaths in the United States and three times more lethal than breast cancer. It is usually not diagnosed until its advanced stages and has come to be known as the “silent killer.”
Pinpointing the exact location of a cancer is needed for some types of cancer. Got ovarian cancer? Remove both ovaries. A woman can live without her ovaries (though major bummer if the woman is young and wanted kids). But suppose an early stage pancreatic cancer becomes detectable via blood test. Well, you need your pancreas. A blood test doesn't tell exactly where the cancer is located. How hard will it be to find cancers detected at very early stage by blood tests?
I'm excited about the prospects for early stage cancer detection and removal. But I'm even more excited by a different approach: rejuvenate and rev up immune systems to create extreme anti-cancer cells. Getting medically cured of specific diseases is not as exciting as enhancing your body so it can fix itself. But we are going to get both advances. The better testing will come sooner and is already happening. Vaccines against cancers will also come sooner but won't be anywhere near as effective as rejuvenating and enhancing the immune system.
We need immune system rejuvenation anyway so that we don't have to worry about getting killed by influenza or a bacterial infection when we get older. Immune system rejuvenation will reduce the frequency of infections, severity of infections, frequency of auto-immune diseases, and also frequency of cancer.
If you have 5 specific genetic variations in your genes then Your risk of prostate cancer goes up by 4 to 5 times.
WINSTON-SALEM, N.C. – New genomics research has found that a simple blood test can determine which men are likely to develop prostate cancer. Researchers at Wake Forest University School of Medicine and colleagues found that five genetic variants previously associated with prostate cancer risk have a strong cumulative effect.
Reporting in New England Journal of Medicine, researchers found that a man with four of the five variants has an increased risk of 400 to 500 percent compared to men with none of the variants. The researchers then added a family history of prostate cancer to the equation – for a total of six risk factors. A man with at least five of the six factors had increased risk of more than 900 percent.
The article was published “Online First” today and will be included in the Feb. 28 print issue.
The scientists say each variant was independently associated with prostate cancer risk and that the variants are fairly common in the population. Together, these five variants and a family history accounted for almost half (46 percent) of prostate cancer patients. The study involved analyzing DNA samples from 2,893 men with prostate cancer and 1,781 healthy individuals of similar ages – all participants of a prostate cancer study in Sweden.
But what is the point of knowing you are doomed? We might be lucky and find out that people who have greater genetic risk of this or that disease would especially benefit from a particular risk lowering diet. Also, these risk genes are obvious targets for drug development to create drugs that suppress or enhance target genes to cancel out their disease risk.
Cheap DNA testing technology is producing a lot more research studies where many different genetic variations are found to be important at a time. Other studies will find gene combinations for risk of other diseases.
According to the researchers, this is the first time that anyone has been able to demonstrate how a combination of genes affect the risk of developing the disease. Scientists the world over are currently searching for gene combinations behind common diseases like cancer, diabetes and asthma.
"For the first time, this type of study has made it possible to develop a clinically viable gene test," says Professor Grönberg.
The study was based on genetic analyses of approximately 4,800 Swedish men, of whom 3,000 had prostate cancer and 1,800 had no prostate cancer diagnosis.
Once genetic tests for a great many diseases hit the market I expect to see a lot more interest groups to form to lobby for faster research. Once you know exactly what sort of ticking genetic time bombs you've got inside of you one response is to become a big supporter of research that aims to slay your big risks before they slay you.
Investigators found 16 SNPs in five different regions of human chromosomes 8 and 17 that were more common to men with prostate cancer than those without the disease. The individual changes were ones previously linked to prostate cancer and other diseases, a good indication, the scientists say, that they were on the right track.
To create their panel, the scientists chose the best SNPs from each of the five regions and tested their cumulative effect on prostate cancer risk. As the number of associated SNPs increased, so did risk. Men with four or more of these SNPs were nearly 4.5 times more likely to have prostate cancer.
They did not compare all genetic variations. They were only looking at single nucleotide polymorphisms (SNPs: single letter differences in DNA sequences). SNPs are not the only kind of genetic variation. Plus, they were only looking at a subset of all SNPs. This suggests that other genetic risk factors for prostate cancer are waiting to be found and the same is true for other types of cancer.
Update: In just a few months you guys will be able to get yourself tested for your prostate cancer risk.
A company formed by researchers at Wake Forest University School of Medicine is expected to make the test available in a few months, said Karen Richardson, a Wake Forest spokeswoman. It should cost less than $300.
This signals the beginning of a long awaited revolution in medical genetics.
This is, some medical experts say, a first taste of what is expected to be a revolution in medical prognostication.
I think a lot of people are going to be upset to learn which specific high risks they face. Well, in preparation for that day support the more rapid development of treatments to cure all the causes of aging and age-related diseases.
At the the third conference for Strategies for Engineered Negligible Senescence (SENS) Dr. Zheng Cui of Wake Forest University reported on impressive progress of his research team toward use of immune cells to defeat cancer.
Attendees at SENS3 heard first-hand about an extremely exciting approach to cancer treatment that has not yet hit the scientific literature or the press. In 2003, Dr. Zheng Cui and his colleagues at the Comprehensive Cancer Center of Wake Forest University reported the discovery of mice with immune cells that rendered them invulnerable to cancer: they had been intentionally giving mice cancer by injecting them with virulent cancer cells as part of a separate study, when they discovered a single mouse in the colony that was completely immune to the invasive cells.
His curiosity piqued, Dr. Cui went on to show that it could resist multiple rounds of such injections, and were so impressed that they used him to father a whole colony of mice, all of whom shared this remarkable invulnerability to cancer. Based on that ability, he calls them spontaneous regression/complete resistance (SR/CR) mice.
Last year, Dr. Cui electrified the world when he showed that the new strain's cancer-fighting abilities were caused by a particular subset of their immune cells -- members of a class of white blood cell known as neutrophil granulocytes.
You might be among the lucky few who have immune systems with especially high competence at defeating cancer.
At SENS3, Dr. Cui presented the next logical step in his research: work demonstrating the existence of, and characterizing, high-potency cancer-killing granulocytes in humans.
Dr. Cui's team first went looking for the existence of potent cancer-killing granulocytes in a group of healthy volunteers. This was done by testing the volunteers' granulocytes' ability to destroy cancer cells in a petrie dish. They found that, unlike in mice (who seem to have an all-or-nothing effect), there appears to be a classical bell-shaped distribution of cancer-killing ability in the granulocytes of people in the population: a few people have white blood cells extremely weak cancer-killing activity, the great majority have an 'average' competence, and a very small group of outliers have the kind of overwhelming search-and-destroy activity (at least in a test tube!) that is seen in the SR/CR mice.
Winter gives you cancer by weakening your immune system.
Surprisingly, they found that the ability of peoples' granulocytes to kill cancer is very sensitive to the season. Looking at the efficacy of granulocytes drawn at samples taken year round, he found that the activity is strong in the sunnier months (May to September) and falls off dramatically in the gloomier ones (November through April). The reason for this effect is unknown, but it could be connected to other things that vary with the number of hours of daylight and that are connected to cancer risk, such as the circadian-rhythm hormone melatonin or the "sunshine vitamin," vitamin D3.
He also found that the cancer-killing capacity could be "abolished" by stress: in one anecdote, a grad student from his lab at Wake Forest had been tested just after making his first presentation at a scientific conference, and the normally high level of cancer-fighting activity in his granulocytes was severely depressed. Re-testing him several days later, the activity of his granulocytes had bounced back to normal.
Stress is bad. Stress gives you cancer. But then that only makes sense. As Joe Jackson sang "Everything gives you cancer".
An immune method to defeat cancer would be great. Cui's about to start a clinical trial on 22 humans to try to see if immune system components from people with super immune systems can defeat cancer when separated out and injected into people with cancer.
Cui took blood samples from more than 100 people and mixed their granulocytes with cervical cancer cells. While granulocytes from one individual killed around 97 per cent of cancer cells within 24 hours, those from another healthy individual only killed around 2 per cent of cancer cells. Average cancer-killing ability appeared to be lower in adults over the age of 50 and even lower in people with cancer. It also fell when people were stressed, and at certain times of the year.
Maybe most of the increase of cancer with age is due to weakening immune systems. Immune system rejuvenation would probably reduce the incidence of cancer. Also, these people who have super anti-cancer immune systems have something that can be replicated in other people. Maybe gene therapy or vaccines could tune up our immune systems to make them more like the immune systems of the rare few whose immune systems are especially aggressive against cancer.
Neutrophils and macrophages, as major components of infiltrating leukocytes, migrate to the site of cancer cells, capture the cancer cells by making tight physical contact with the cancer cell surface and destroy them via cytolysis. The leukocytes of these cancer-resistant mice can be used as therapeutic agents to cure several forms of highly aggressive cancers in wild type mice without any sign of adverse side effects. This leads to the apparent question of whether we can find cancer-resistant humans to test a similar cancer treatment via allogenic innate white cell transfer. Using a newly developed in vitro assay to measure the ability of white cells to kill various cancer cell line targets, we surveyed human volunteers and found that a significant number of healthy humans have cancer-killing activity (CKA) similar to that of cancer-resistant mice. There seems to be a bell-shaped distribution of CKA in the population of healthy humans. The CKA average appears to be lower in older human populations and to be even lower in human cancer patients. The CKA can also be abolished by stress and change of seasons. Based on these findings and the ability to screen for cancer-resistant humans as allogenic white cell donors, we proposed a new cancer treatment strategy, termed "GIFT" (Granulocyte InFusion Therapy), that will soon enter phase II clinical trials.
Angiogenesis inhibitors work against cancer by blocking the development of new blood vessels into tumors so that tumors can't grow. The hope with angiogenesis inhibitors is that they will have less side effects than conventional chemotherapy and radiation. Given that chemo and radiation cause severe side effects a treatment can be better and still have pretty substantial side effects. Angiogenesis inhibitors turn to out to be capable of causing lethal side effects.
Angiogenesis inhibitors, drugs that block a tumor's development of an independent blood supply, have been touted as effective cancer fighters that result in fewer side effects than traditional chemotherapy. However, a new study by researchers at UCLA's Jonsson Cancer Center has shown that one method of blocking blood-supply development could result in serious and potentially deadly side effects.
The UCLA researchers blocked angiogenesis factor VEGF in a type of cell in mice and found that the mice eventually suffered heart attacks as a result.
Several newly developed angiogenesis inhibitors work by blocking vascular endothelial growth factor (VEGF), an important signaling protein that spurs the growth of new blood vessels. Avastin, an angiogenesis inhibitor approved by the Food and Drug Administration for colon and lung cancers, inhibits angiogenesis by blocking VEGF signaling from outside the cell. UCLA researchers wanted to know what happened when VEGF signaling was blocked from within endothelial cells, a mechanism used by some small-molecule drugs currently being tested in late-phase clinical trials.
The result was unexpected and sobering. More than half of the mice in the study suffered heart attacks and fatal strokes, while those that remained alive developed serious systemic vascular illness, said Luisa Iruela-Arispe, a professor of molecular, cell and developmental biology and director of the Cancer Cell Biology program at UCLA's Jonsson Cancer Center.
The study appears Aug. 24 in the prestigious peer-reviewed journal Cell.
This result suggests humans might suffer more complications from the long term use of anti-angiogenesis compounds.
"This was an extremely surprising result," said Iruela-Arispe, past president of the North American Vascular Biology Organization and a national expert on angiogenesis. "I think this study is cause for some caution in the use of angiogenesis inhibitors in patients for very long periods of time and in particular for use of those inhibitors that block VEGF signaling from inside the cell."
Anti-angiogenesis compounds block the growth of cancers and therefore in many cases won't cure cancer. So people who take anti-angiogenesis compounds have to take them for many years. Hence long term side effects eventually become an issue. However, if you have an otherwise fatal cancer running a risk of blood clots or even a heart attack can be a price worth paying.
About 5 percent of patients taking Avastin develop blood clot-related side effects, Iruela-Arispe said. But because Avastin was approved only three years ago, it is unclear what side effects may occur when patients remain on the drug for many years, she said.
Anti-angiogenesis drugs side effects are acceptable only because those side effects are milder compared to even more undesirable alternatives such as dying sooner or experiencing even greater side effects from chemotherapy and still dying. We need anti-cancer treatments that are far milder while at the same time producing much higher cure rates.
To cure cancer the key piece we need is much more selective ways to deliver treatments aimed precisely at cancer cells while leaving normal cells alone. That's the huge challenge that cancer researchers have been wrestling with for decades. Anti-angiogenesis drugs currently are delivered into the entire body. So they suffer from the same problem that chemotherapy suffers from: They affect too large a range of cells. A more selective way to deliver anti-angiogenesis compounds might involve attaching them to monoclonal antibodies that are targeted to cancer cells. That would get anti-angiogenesis compounds to concentrate near cancer cells. But the anti-angiogenesis compounds need to work their effects against blood vessel cells and blood vessel stem cells that are near cancer cells. A fancier monoclonal antibody mechanism of delivery might activate and release an anti-angiogenesis drug only once the monoclonal antibody attaches to a cancer cell.
Currently a diagnosis of pancreatic cancer is almost always a death sentence. Pancreatic cancer causes little or no symptoms until it has spread and mutated so much that it can't be stopped. If we could only diagnose this cancer much sooner the potential exists to go remove it in a small area and get a cure in most cases. Well, some scientists and technologists at Northwestern University have discovered that a biopsy of the duodenum (the top part of the small intestine which the stomach empties into) can provide a method to do very early diagnosis for pancreatic cancer.
EVANSTON, Ill. --- Optical technology developed by a Northwestern University biomedical engineer shown to be effective in the early detection of colon cancer now appears promising for detecting pancreatic cancer, the fourth most common cause of cancer deaths in the United States.
Known as a silent killer, with no method of early detection, pancreatic cancer spreads rapidly and seldom is detected in its early stages. The new technique could lead to the first screening method for pancreatic cancer in asymptomatic patients, said Vadim Backman, developer of the technology and professor of biomedical engineering at Northwestern’s Robert R. McCormick School of Engineering and Applied Science.
Backman and Yang Liu, a former graduate student of Backman’s, teamed up with physicians at Evanston Northwestern Healthcare (ENH) to test the technique in a pilot study of 51 patients. The researchers found they could detect both early- and advanced-stage pancreatic cancer without touching or imaging the pancreas.
The extraordinarily sensitive technique, which is minimally invasive and takes advantage of certain light-scattering effects, can detect abnormal changes in cells lining the duodenum even though the cells appear normal when examined with a conventional microscope. The results, which will be published in the Aug. 1 issue of the journal Clinical Cancer Research, show that the changes accurately predict the presence of cancer.
So they developed a better way to examine cells to identify abnormal cells. Then they used that better technology to examine duodenal cells because it is easier to reach the duodenum to get the cell sample than it is to reach the pancreas. Luckily, the duodenum shows abnormal cells when the pancreas (which connects to the duodenum) has early stage cancer cells. All very good.
What I want to know: How did they reach the duodenum? Can this be done by snaking a tube through the mouth and down through the stomach?
In the study, biopsies of normal-looking tissue were taken from the duodenum near the opening of the pancreatic duct for analysis. For each sample, light is shined on the tissue. The light scatters and some of it bounces back to sensors in the fiber-optic probe. A computer analyzes the pattern of light scattering, looking for the “fingerprint” of carcinogenesis in the nanoarchitecture of the cells.
The researchers found the technique identified with 100 percent accuracy each person who had a resectable cancerous tumor in the pancreas. (Resectable means the tumor can be removed surgically, which in this study is defined as stage 1 or 2 tumors.) Some people were identified who did not have a tumor; it is uncertain whether this is a false finding or if it means those people could be at risk for developing pancreatic cancer and need to be watched closely.
This pair of optical tests also produced excellent results in detecting colon cancer.
The method combines two complementary technologies developed by Backman and colleagues in his lab: four-dimensional elastic light-scattering fingerprinting (4D-ELF) and low-coherence enhanced backscattering spectroscopy (LEBS). The researchers found that the two combined work better than one alone in pancreatic cancer screening.
The success of the pancreatic cancer screening study follows on the heels of extremely positive results in studies using the two optical technologies for the early detection of colon cancer.
What I want to know: How often would we need to get tested for pancreatic and colon cancer to assure that new cancers would always get caught at early enough stages to be curable? How fast does a pancreatic cancer pass through its first stage into later stages? My guess is that the answer varies considerably from case to case.
What we really need are cancer tests for the entire body that can work pretty close to continuously. Imagine an injection of a cancer detection nanobot that would produce a visible symptom (how about blue and green spots on your hand or face?) when it found a cancer. Then a blood sample could isolate some nanobots and an instrument could download the collected information from the nanobots.
We face another problem with highly sensitive techniques for early cancer detection: We have lots of very small cancers in tiny nodes that are stuck at very small sizes because they have not mutated to generate new blood vessels (ie they do not secrete angiogenesis compounds). The most sensitive methods imaginable for detecting cancers would detect too many. The vast majority of detected abnormal cells would not constitute a threat - at least not for many years. Attempts to find and remove all these very small cancers would involve surgery on many organs and the little cancer nodes might be hard for surgeons to find. So we need cancer finding technology that can discriminate between high and low risk cancers.
A molecularly engineered therapy selectively embeds a gene in pancreatic cancer that shrinks or eradicates tumors, inhibits metastasis, and prolongs survival with virtually no toxicity, researchers from The University of Texas M. D. Anderson Cancer Center report in the July 9 edition of Cancer Cell.
"This vehicle, or vector, is so targeted and robust in its cancer-specific expression that it can be used for therapy and perhaps for imaging," notes senior author Mien-Chie Hung, Ph.D., professor and chair of M. D. Anderson's Department of Molecular and Cellular Oncology.
The researchers call the system a versatile expression vector - nicknamed VISA. It includes a targeting agent, also called a promoter, two components that boost gene expression in the target tissue, and a payload - in this case a gene known to kill cancer cells. It's all packaged in a fatty ball called a liposome and delivered intravenously.
Researchers are working with M. D. Anderson clinicians to move the system, developed and tested in mouse models of pancreatic cancer, to a Phase I clinical trial.
Future gene therapies will become much more complex and sophisticated. We will likely witness the development of multi-gene gene therapies that are akin to complex computer programs. When injected into each cell the genes and their protein products will sense whether the cell is cancerous and only kill or reprogram cancer cells.
Currently pancreatic cancer is highly lethal.
About 37,000 cases of pancreatic cancer are diagnosed annually in the United States. Early diagnosis is extremely difficult, so the disease is often discovered at a late stage after it already has spread, or metastasized. Fewer than 4 percent of pancreatic cancer patients survive five years after diagnosis, one of the lowest cancer survival rates.
Those horrible odds show why pancreatic cancer patients ought to have the right to try experimental gene therapies without waiting for government approval for therapies. Given a diagnosis of pancreatic cancer I'd want to try any sort of experimental gene therapy or other experimental therapy. With so little time left to live the downsides would be small.
Cold Spring Harbor, N.Y. -- Cold Spring Harbor Laboratory (CSHL) researchers led by Daniel Nolan and Assistant Professor Vivek Mittal have found that bone marrow (BM) derived endothelial progenitor cells (EPCs) play a critical role in the early stages of tumor progression and that eliminating EPCs stops cancer growth. Using sophisticated high-resolution microscopy and flow cytometry, they zeroed in on the earliest stages of cancer progression and identified the role of EPCs in generating blood vessels that allow cancers to grow. “If we selectively blocked the EPCs, tumors were unable to make blood vessels and could not sustain their own growth,” said Vivek Mittal, CSHL Assistant Professor.
But how to use this knowledge therapeutically? Usually early stage cancers go undetected. So suppression of stem cells in early stage cancers isn't a practical way to stop cancers. Scientists already know (and Judah Folkman gets much of the credit) that cancer cells mutate to release angiogenesis compounds to stimulate blood vessel growth. Some anti-cancer drugs work as angiogenesis inhibitors. We need more such compounds.
What this result makes me wonder: Once we can get youthful stem cell therapies will the stem cells up our cancer risk even if the stem cells themselves do not become cancerous? Maybe aging stem cells reduce the ability of tumors to spur blood vessel generation that tumors need to grow. Maybe young stem cells will more vigorously respond to angiogenesis compounds that cancer cells secrete and will build blood vessels more rapidly.
Some of the slowing down in the body that happens with age is likely an adaptation designed to reduce the risk of cancer spread. We need highly effective cures for cancer that cause little collateral damage. Those cancer cures will lower the risks of future rejuvenation therapies.
Studies of human tumor cells implanted in mice have shown that the abnormal activation of four genes drives the spread of breast cancer to the lungs. The new studies by Howard Hughes Medical Institute researchers reveal that the aberrant genes work together to promote the growth of primary breast tumors. Cooperation among the four genes also enables cancerous cells to escape into the bloodstream and penetrate through blood vessels into lung tissues.Although shutting off these genes individually can slow cancer growth and metastasis, the researchers found that turning off all four together had a far more dramatic effect on halting cancer growth and metastasis.
Each individual drug under development most often gets tested by itself to determine its effectiveness. Drug developers realize this means they miss useful drugs. But since thousands of drugs exist the task of choosing drugs to try in combination seems impossible. The number of combinations becomes too great if one has to choose sets of 2 or 3 or 4 drugs to test in combination. But as this report shows, genetic research can show that a group of genes drive development of a disease. This allows researchers to narrow their focus toward drugs that target each of those genes. Then the potential combinations of drugs to test shrinks down to a practically testable set and the likelihood of finding synergistic combinations of drugs goes up by orders of magnitude.
In this case the researchers were lucky because 2 of the 4 genes they identified already have existing drugs that target them.
In the newly published experiments, the researchers also found that they could reduce the growth and spread of human breast tumors in mice by simultaneously targeting two of the proteins produced by these genes, using drugs already on the market. The researchers are exploring clinical testing of combination therapy with the drugs—cetuximab (trade name Erbitux) and celecoxib (Celebrex)—to treat breast cancer metastasis.
Think about that. Other existing drugs might be useful in combinations against cancer and we simply do not yet have enough genetic research information to point ourselves toward them.
This work builds on previous work that identified 18 genes involved in cancer metastasis. They narrowed their focus to 4 of those 18.
In an earlier study, Massagué and his colleagues had identified 18 genes whose abnormal activity is associated with breast cancer's ability to spread to the lungs. In the new study published in Nature, Massagué and his colleagues at Sloan-Kettering, along with researchers from Hospital Clinic de Barcelona and the Institute for Research in Biomedecine in Spain, focused on four of these genes. These genes, which code for proteins called epiregulin, COX2, and matrix metalloproteinases 1 and 2, were already known to help regulate growth and remodeling of blood vessels, said Massagué.
Blood vessel growth is key for cancer growth. Dr. Judah Folkman at Harvard Medical School has spent his career demonstrating that genes and proteins involved in blood vessel formation (angiogenesis) are useful targets for anti-cancer treatments. Anti-angiogenesis drugs are now useful against some forms of cancer.
Separate tests of these drugs against cancer did not suggest that in combination they'd turn out useful.
Two drugs already on the market act directly on proteins produced by the genes Massagué's group had been studying. Cetuximab is an antibody that blocks the action of epiregulin and is used to treat advanced colorectal cancer. Celecoxib is an inhibitor of COX2 that is used as an anti-inflammatory, and is being tested in clinical trials against many types of cancer. The researchers also tested whether cetuximab and celecoxib would work effectively in concert to reduce metastasis in mice.“We found that the combination of these two inhibitory drugs was effective, even though the drugs individually were not very effective," said Massagué. “This really nailed the case that if we can inactivate these genes in concert, it will affect metastasis,” he said.
Research into interacting sets of genes will point us toward many more drug targets for cancer and for other diseases as well. Improvements in technologies for gene chips and other tools for watching gene activity will speed up the rate at which scientists can identify, monitor, and tweak sets of genes involved in disease progression. Therefore the rate at which we find relationships between genes will accelerate. In the next 10 years I expect that every single gene involved in cancer growth and spread will become a target of drug development. Once we have drugs that target large sets of genes I expect many cancers to become controllable and some to become curable.
What we really need in order to cure all cancers are gene therapies that will go into cancer cells and fix some of the mutations that make cells become cancers. This research also helps work in that direction because it helps identify genes to target for gene therapy.
The range of mutations that can drive cancer growth could be much wider than thought. An international research effort called the Cancer Genome Project has identified around 120 new genes that contain mutations promoting the disease.
"This is a lot more cancer genes than we expected to find," says Michael Stratton of the Wellcome Trust's Sanger Institute in Cambridge, UK, one of the leaders of the research.
The discovery of a single gene that contributes to cancer used to constitute a big step forward. Not any more. Declining costs for DNA sequencing make possible much bigger searches for cancer promoting mutations.
These scientists focused their attention on enzymes called kinases which are involved in regulating other enzymes and other cellular components. This was done by sequencing a quarter billion letters of DNA.
Scientists at the Wellcome Trust Sanger Institute, where one-third of the human genome was sequenced, have now pioneered decoding the sequence of cancer genomes. They have carried out the broadest survey yet of the human genome in cancer by sequencing more than 250 million letters of DNA code, covering more than 500 genes and 200 cancers.
The continued decline in the cost of DNA sequencing will eventually make the discovery of important mutations (whether harmful or beneficial) incredibly easy. Scientific instrumentation advances are more important than any one biomedical research discovery because the instrumentation advances make the discoveries possible.
Howard Hughes Medical Institute researchers have developed two strategies to reactivate the p53 gene in mice, causing blood, bone and liver tumors to self destruct. The p53 protein is called the “guardian of the genome” because it triggers the suicide of cells with damaged DNA.
Inactivation of p53 can set the stage for the development of different types of cancer. The researchers' findings show for the first time that inactivating the p53 gene is necessary for maintaining tumors. While the researchers caution that cancers can mutate to circumvent p53 reactivation, they believe their findings offer ideas for new approaches to cancer therapy.
The research was carried out independently by two Howard Hughes Medical Institute (HHMI) research teams led by Tyler Jacks at the Massachusetts Institute of Technology and Scott Lowe at Cold Spring Harbor Laboratory. Both papers were published online January 24, 2007, in advance online publication articles in the journal Nature.
The techniques the teams used to reactivate the p53 gene could not be used therapeutically in humans because they genetically engineered the mice to have their p53 genes controllable with drugs.
To reactivate p53, Lowe and his colleagues used a genetic technique they had developed to induce an aggressive form of liver cancer in mice. Although they had inactivated p53 in the mice, they genetically engineered the mice so that they could reverse p53 inactivation by giving the animals the antibiotic doxycycline. They suppressed p53 protein levels by using RNA interference (RNAi) that had been modified so that RNAi could be switched off by the antibiotic. The RNA interference technology was developed in collaboration with HHMI investigator Gregory Hannon at Cold Spring Harbor Laboratory.
When the researchers reactivated p53 in the mice they found that the liver tumors completely disappeared. “This was quite surprising,” said Lowe. “We were working with a very advanced, aggressive tumor, but when we reestablished p53, not only did it stop growing, it went away.
The most obvious way to try to duplicate this result in humans would be to send in p53 genes in some sort of gene therapy delivery package. But we lack the technologies needed to do that. Gene therapy delivery is a hard problem.
The way that p53 activation stopped the cancers was surprising. It made cells go into a senescent state rather than to commit suicide. But once in the senescent state the immune system in the mice attacked these cells.
“But the second surprise—and perhaps the more scientifically interesting one—was why the tumor went away,” said Lowe. “We expected the tumor cells to undergo programmed cell death, or apoptosis. But instead, we saw evidence for a very different process that p53 also regulates—senescence, or growth arrest. What really excited us was evidence that this senescence somehow triggered the innate immune system to kill the tumor cells.” Involvement of the innate immune system suggests there may be an unknown mechanism by which cancers can trigger the immune system, he said. Lowe and his colleagues are now exploring how the innate immune system might be enlisted against cancer.
How do cancer cells suppress the immune system to prevent it from attacking them? These mice make for a good research model to try to figure out how cancer cells protect themselves from immune attack. Once scientists know how that works they can develop therapies that'll basically block the immune suppression mechanisms used by cancer cells. Then cancer vaccines would become far more potent.
For some types of cancer the gene for p53 might still be intact but deactivated. A drug might be able to reactivate it. But in other types of cancer p53 is probably so mutated that it can't be reactivated. Delivery of replacement genetic material might be the only solution. But that approach runs up against the problem of how to deliver a replacement gene into every single cancer cell in a person's body.
Genetically engineered copies of p53 could find use in human stem cell therapies and in the development of replacement organs. Replacement cells could have not only normal copies of p53 but also additional copies which will activate only in the presence of a particular drug. That way if cells ever go cancerous due to mutations in regular p53 genes a back-up set of p53 genes could get activated by a prescription antibiotic or some other drug. Think of such genetically engineered p53 genes as akin to emergency brakes in cars. If your main cancer brakes give way additional sets of cellular brakes could get turned on.
January 16, 2007 - Edmonton - DCA is an odourless, colourless, inexpensive, relatively non-toxic, small molecule. And researchers at the University of Alberta believe it may soon be used as an effective treatment for many forms of cancer.
One qualifier to the above statement: Whether dichloroacetate (DCA) would really be non-toxic when used in therapeutic doses against cancer remains to be seen. When used to treat a genetic disorder involving high lactic acid DCA caused peripheral neuropathy. DCA inhibits a kinase enzyme that deactivates an enzyme called pyruvate dehydrogenase (PDH) which is involved in mitochondrial metabolism (i.e, it is involved in sugar breakdown to make energy).
Dr. Evangelos Michelakis, a professor at the U of A Department of Medicine, has shown that dichloroacetate (DCA) causes regression in several cancers, including lung, breast and brain tumors.
Michelakis and his colleagues, including post-doctoral fellow Dr. Sebastian Bonnet, have published the results of their research in the journal Cancer Cell.
Many cancer cells do not break sugar down completely. They just do a step called glycolysis. They do not do a step called the Krebs cycle (aka the citric acid cycle or tricarboxylic acid cycle or TCA cycle) which extracts all the energy out of sugar molecules to make energy carrier molecules called NADH and ATP. This was first observed about cancer all the way back in the 1930s. Up until now the assumption to explain this was that cancer cells lost that ability. But this result suggests that not only do cancer cells suppress that ability but that suppression helps them grow uncontrollably.
Pyruvate dehydrogenase (PDH) synthesizes acetyl-CoA which is used in the first step of the TCA cycle in mitochondria. If DCA has either toxicity problems or problems with achieving sufficient doses that does not defeat this approach to anti-cancer drug development. The kinase that DCA blocks could become a target for drug development. A drug that would disable that kinase would likely activate mitochondria in cancer cells just like DCA does.
I remember a scientist telling me decades ago that classic intermediary metabolism doesn't get the attention it deserves because everyone was rushing into genetics. Many scientists decided that there was little of interest left to learn from studying the main pathways of energy metabolism. This result argues for his view. How can we get all the way to the year 2007 without noticing sooner the powerful results from a simple long known molecule?
Michelakis decided the conventional wisdom on cancer and mitochondria might be wrong and decided to test it.
Until recently, researchers believed that cancer-affected mitochondria are permanently damaged and that this damage is the result, not the cause, of the cancer. But Michelakis, a cardiologist, questioned this belief and began testing DCA, which activates a critical mitochondrial enzyme, as a way to "revive" cancer-affected mitochondria.
The results astounded him.
Michelakis and his colleagues found that DCA normalized the mitochondrial function in many cancers, showing that their function was actively suppressed by the cancer but was not permanently damaged by it.
More importantly, they found that the normalization of mitochondrial function resulted in a significant decrease in tumor growth both in test tubes and in animal models. Also, they noted that DCA, unlike most currently used chemotherapies, did not have any effects on normal, non-cancerous tissues.
No one single molecule is going to cure all cancers by itself. But combinations of compounds where all have toxicity highly specific to cancer cells will certainly end up curing a great many cancers. Monoclonal antibodies targetted at cancers, anti-angiogenesis compounds that block blood vessel growth in cancers, gene therapies that activate in cancer cells and assorted other compounds such as DCA are going to cure many cancers when used in combination.
"I think DCA can be selective for cancer because it attacks a fundamental process in cancer development that is unique to cancer cells," Michelakis said. "Cancer cells actively suppress their mitochondria, which alters their metabolism, and this appears to offer cancer cells a significant advantage in growth compared to normal cells, as well as protection from many standard chemotherapies. Because mitochondria regulate cell death - or apoptosis - cancer cells can thus achieve resistance to apoptosis, and this appears to be reversed by DCA."
The suppression of mitochondria might be a way for cancer cells to divide in low oxygen environments found deep in tumors lacking in sufficient vasculature. By turning on mitochondria in these cells their need for oygen is probably increased and that likely contributes to their death. This suggests that DCA might work well in combination with anti-angiogenesis drugs since the ability of anti-angiogenesis drugs to block blood vessel growth will decrease the amount of oxygen available to tumors and therefore make more cells in tumors susceptible to the effects of DCA.
DCA (aka Ceresine) has a big problem: It is not patentable and hence provides little incentive for commercial companies to raise money to fund clinical studies to develop it as an anti-cancer drug. People who are philosophically opposed to patents ought to take note of this.
Furthermore, the DCA compound is not patented or owned by any pharmaceutical company, and, therefore, would likely be an inexpensive drug to administer, Michelakis added.
However, as DCA is not patented, Michelakis is concerned that it may be difficult to find funding from private investors to test DCA in clinical trials. He is grateful for the support he has already received from publicly funded agencies, such as the Canadian Institutes for Health Research (CIHR), and he is hopeful such support will continue and allow him to conduct clinical trials of DCA on cancer patients.
If DCA is on the market in less regulated countries then maybe it'll get tried out in human cancer patients under less restrictive regulatory regimes.
Evangelos Michelakis of the University of Alberta in Edmonton, Canada, and his colleagues tested DCA on human cells cultured outside the body and found that it killed lung, breast and brain cancer cells, but not healthy cells. Tumours in rats deliberately infected with human cancer also shrank drastically when they were fed DCA-laced water for several weeks.
People who have fatal diseases should be allowed to try anything as a treatment.
Not only did the rate of cancer death per 100,000 go down. But the total number of people who died from cancer in the United States went down in 2003 and 2004.
Fewer people died of cancer in 2004 than in 2003, marking the second consecutive year that cancer deaths have declined in the United States, a new American Cancer Society report shows. According to Cancer Statistics 2007, there were 3,014 fewer cancer deaths in 2004 compared to the previous year. The report is published in the latest issue of the ACS journal CA: A Cancer Journal for Clinicians.
That number is much higher than the drop of 369 deaths reported between 2003 and 2002. And that suggests the trend is more than just a statistical blip, experts say.
A decline in deaths from colorectal cancer caused about a third of the total decline. Part of the decline was due to wider use of colonoscopy to remove polyps and catch cancer sooner. But new drugs also are driving down the death rate from colorectal cancer.
Improved treatment has also played a part in lowering the death rate from colorectal cancer, Dr. Neugut said. “There was a revolution in treatment between 1998 and 2000, and revolution is a mild word,” he said. “We went from having one drug to having six or seven good drugs. The cure and survival rates have increased dramatically as a result. The cost of care has also gone up, but you get what you pay for.”
The toal number of cancer deaths declined in spite of both an aging population and a growing population.
The death rate from cancer has been falling by slightly less than 1 percent a year since 1991, but until 2003 the actual number of deaths kept rising because the population was growing and aging. Then, in 2003, the cumulative drop in death rates finally became large enough to outpace aging and population growth.
Cancer deaths can be driven down further by vaccines against viral causes of cancer and antibiotics against bacterial causes. The new Gardasil vaccine against human papilloma virus will lower the incidence of cervical cancer. Also, vaccines against hepatitis B can lower the incidence of liver cancer. Wider testing for the helicobacter pylori bacteria infections of the stomach could lead more to take antibiotics to cure it. That would lower the incidence of stomach cancer. Identification of more pathogenic causes of cancer will lead to the development of still more ways to prevent cancer.
In 2003 and 2004, the cancer death rate declined by about 2 percent each year -- more than offsetting the effects of aging and population growth.
We are goign to witness an acceleration in the decline of the cancer death rate. Combinations of anti-angiogenesis factors to stop blood vessel growth in tumors will stop some cancers. Immune approaches such as monoclonal antibodies carrying toxins will get better.
We are also going to see some big successes with the use of stem cells against cancer. A stem cell treatment was used to locally activate chemo agents mostly at tumor sites and this cured all treated mice of neuroblastoma cancer.
Researchers at City of Hope and St. Jude Children's Research Hospital may have found a way to treat cancers that have spread throughout the body more effectively. They used modified neural stem cells to activate and concentrate chemotherapeutic drugs predominately at tumor sites, so that normal tissue surrounding the tumor and throughout the body remain relatively unharmed.
The neural stem cells are attracted to compounds that tumours secret. Possibly the compounds which attract the neural stem cells are angiogenesis compounds that stimulate blood vessel growth. Or perhaps the damaged nature of cancer cells cause them to secrete lots of free radical compounds that signal damage which stem cells rush in to repair.
Most chemotherapy drugs affect both normal and cancerous tissue, which is why they also are toxic to naturally fast-growing cells in the body such as hair follicles and intestinal cells. Aboody and her colleagues have developed a two-part system to infiltrate metastatic tumor sites, and then activate a chemotherapeutic drug, thereby localizing the drug's effects to the tumor cells.
The technique takes advantage of the tendency for invasive tumors to attract neural stem cells. The researchers injected modified neural stem/progenitor cells into immunosuppressed mice that had been given neuroblastoma cells, which then formed tumors. After waiting a few days to allow the stem cells to migrate to the tumors, researchers administered a precursor-drug. When it reached the stem cells, the drug interacted with an enzyme the stem cells expressed, and was converted into an active drug that kills surrounding tumor cells. The precursor-drugs were administered for two weeks, then after a two-week break, a second round of stem/progenitor cells and drugs were administered.
One hundred percent of the neuroblastoma mice appeared healthy and tumor-free at six months. Without treatment, all the neuroblastoma mice died within two-and-a-half months.
The results hold promise for treating solid tumors that metastasize including neuroblastoma, which represents 6 percent to 10 percent of all childhood cancers worldwide, with higher proportions in children under 2 years of age.
Cancer is not an unsolvable problem. To study and develop treatments for cancer scientists are getting far more powerful tools. Nanotechnologies such as microfluidics are going to accelerate the rate of progress of biomedical research by orders of magnitude. If you do not get cancer in the next 20 years you aren't going to die from it. Our tools are going to become far more powerful than the disease.
COLUMBUS , Ohio – A pattern of micro molecules can distinguish pancreatic cancer from normal and benign pancreatic tissue, new research suggests.
The study examined human pancreatic tumor tissue and compared it to nearby normal tissue and control tissue for levels of microRNA (miRNA). It identified about 100 different miRNAs that are present usually at very high levels in the tumor tissue compared with their levels in normal pancreatic tissue.
Each of these miRNA has a unique short sequence of RNA letters. RNA is like DNA except it delivers signals and instructions around inside of cells. That there are so many kinds of miRNAs at higher levels is useful for the development of anti-cancer treatments.
These researchers envision anti-cancer drugs aimed at the miRNAs which occur at higher concentrations in cancers.
“Our findings show that a number of miRNAs are present at very different levels in pancreatic cancer compared with benign tissue from the same patient or with normal pancreatic tissue,” says principal investigator Thomas D. Schmittgen, associate professor of pharmacy and a researcher with the Ohio State's Comprehensive Cancer Center.
“Most are present at much higher levels, which suggests that developing drugs to inhibit them might offer a new way to treat pancreatic cancer. It also means that a test based on miRNA levels might help diagnose pancreatic cancer.”
I see a more sophisticated way to use this information to develop anti-cancer therapies: Develop gene therapies that would go into cells in organs which have cancer cells. The gene therapies would have sequences that match with the miRNA sequences involved in cancer. If enough miRNA sequences match with corresponding gene sequence DNA segments this binding could be used to activate the gene therapy in a cell to kill that cell.
To put it another way: Develop a gene therapy that acts like a computer program that activates in the presence of genetic signals that indicate cancer. This would allow far greater selectivity in killing of cancer cells without killing normal tissue.
Out of about 470 miRNAs currently known these researchers measured the levels of 225 of them. Likely other miRNAs both known and yet to be discovered would help to improve the accuracy of this method of cancer identification.
For this study, the researchers used a technique developed by Schmittgen and a group of colleagues in 2004 to measure miRNA in small tissue samples. The method is based on a technology called real-time PCR profiling, which is highly sensitive and requires very small amounts of tissue, Schmittgen says.
The researchers used the method to compare the levels of 225 miRNAs in samples of pancreatic tumors from patients with adjacent normal tissue, normal pancreatic tissue and nine pancreatic cancer cell lines.
Computer analysis of the data identified a pattern of miRNAs that were present at increased or decreased levels in pancreatic tumor tissue compared with normal tissue. The analysis correctly identified 28 out of 28 pancreatic tumors, 11 of 15 adjacent benign tissues and six of six normal tissues.
Levels of some miRNAs were increased by more than 30- and 50-fold, with a few showing decreased levels of eight- to 15-fold.
We need methods to deliver gene therapy into all the cells in an organ. With such a capability we could periodically get gene therapy that'd wipe out precancerous cells before they even become full blown cancers.
Melanomas aid themselves in their quest to spread to other parts of the body by sending a chemical signal to the sentinel lymph node, the node most susceptible to early spread of the cancer. The signal cripples the sentinel node's immune response, making it more vulnerable to the cancer, UCLA researchers discovered.
However, UCLA scientists were able to reverse the immune suppression by injecting patients with a compound that stimulates an immune response in the node. The discovery, outlined in the recent issue of Nature Reviews/Immunology, provides valuable clues about how melanomas spread and may one day lead to new ways to treat this deadly form of skin cancer, which will strike more than 62,000 Americans this year. About 8,000 will die from the disease.
"Our success in engineering a reversal of the immune suppression may lead to ways to protect melanoma patients before their cancers attempt to spread," said Dr. Alistair Cochran, a professor of pathology and laboratory medicine and surgery, a researcher at UCLA's Jonsson Cancer Center and lead author of the study. "The restoration of the sentinel lymph node to its normal state should make it better able to fight the spread of cancer."
A new treatment would be a valuable tool for oncologists. Most melanoma patients undergo surgery, but few other treatments have proven effective against this aggressive cancer, Cochran said. Chemotherapy doesn't help much, nor do hormonal or vaccine treatments.
Note the mention of failures of cancer vaccines. These latest results might also help point the way toward making cancer vaccines more effective. As researchers find the various mechanisms by which cancer cells disable the immune system they will use this information to develop techniques to prevent this disablement. These techniques will also make anti-cancer vaccines much more effective. Better methods to control the immune system will yield better cancer treatments.
In the first large-scale screen of genetic changes in cancer cells, researchers have found that a typical breast or colorectal tumor results from mutations in about 90 genes, with different sets of mutations producing the same type of cancer. But the many different genetic routes to malignancy share common features that point toward new means of cancer prevention, diagnosis, and treatment.
Previous genetic studies of cancer have concentrated on specific genes or on chromosomal regions. In the September 8, 2006, issue of Science, Howard Hughes Medical Institute (HHMI) investigators Bert Vogelstein at Johns Hopkins University and Sanford D. Markowitz at Case Western Reserve University School of Medicine, together with a team of researchers from The Kimmel Cancer Center at Johns Hopkins and other institutions, report on a radically new way of identifying genes involved in cancer.
They analyzed 13,000 genes in 11 breast cancer tumors and 11 colorectal tumors to come up with the 90 genes of interest in cancer. One obvious next step would be to repeat this process for more types of cancer and more instances of each type.
While many mutations and genes are involved they fit into a smaller number of pathways that are crucial for the development of cancers. While not mentioned here I'm guessing genes which are involved in producing signals for angiogenesis (growth of new blood vessels) are in their set of 90 genes.
Despite the complexity of the results, a closer examination of the data has started to reveal an underlying order. Many of the genes that are mutated are involved in pathways thought to be important in cancer, such as cell adhesion, movement, and signaling. Each of these pathways relies on multiple genes, and flaws in any of the genes in a pathway may have similar consequences.
“By taking a systems biology approach to connect these genes, we suspect that the complexity will be less than it appears at first sight,” said Vogelstein. “The same 10 or 20 pathways may be altered in every cancer, though the particular mutated genes in these pathways will be different. The picture will become much clearer as the function of these genes and the ways they interact are better worked out.”
They've identified 90 genes involved in cancer. But they do not know what the proteins do which are made by some of these genes. But they now have identified many genes whose proteins can be studied by cancer research labs.
Technological advances only recently made possible the collection of the data which produced these results.
This kind of study could not have been done a few years ago, said Tobias Sjöblom, an HHMI research associate in Vogelstein's lab, who is the lead author of the Science article. But the availability of the human genome sequence and improvements in sequencing and bioinformatics technologies have made it possible to examine the genome of cancer cells in a comprehensive and unbiased manner, he said.
The rate of biotechnological advance is not slowing. Successively better generations of test equipment and software are both accelerating the rate at which genetic and other biological information can be collected and analysed. The rate of advance in understanding of how cancer works was a snail's pace 30 or 40 years ago. The pace now is much faster. 10 years from now with all the instrumentation and software advances that'll happen in the meantime the rate of advance will be blazing. 20 years from now death from cancer should become rare.
A team of researchers at the National Cancer Institute (NCI), part of the National Institutes of Health, has demonstrated sustained regression of advanced melanoma in a study of 17 patients by genetically engineering patients' own white blood cells to recognize and attack cancer cells. The study appears in the online edition of the journal Science on August 31, 2006*.
"These results represent the first time gene therapy has been used successfully to treat cancer. Moreover, we hope it will be applicable not only to melanoma, but also for a broad range of common cancers, such as breast and lung cancer," said NIH Director Elias A. Zerhouni, M.D.
Immunotherapies that are specific to cancer cells are much preferred over chemotherapies and radiation therapies that also trash normal cells throughout the body. Gene therapy that programs immune cells to attack only cancer cells will cause far fewer harmful side effects. If scientists can find surface protein features specific to all cancers (and it is not clear to me that this is possible) then genetically engineered immunotherapies will eventually cure all cancers.
Not all patients benefitted but it looks like a cure for 2 of them.
Thus, NCI researchers, led by Steven A. Rosenberg, M.D., Ph.D., sought an effective way to convert normal lymphocytes in the lab into cancer-fighting cells. To do this, they drew a small sample of blood that contained normal lymphocytes from individual patients and infected the cells with a retrovirus in the laboratory. The retrovirus acts like a carrier pigeon to deliver genes that encode specific proteins, called T cell receptors (TCRs), into cells. When the genes are turned on, TCRs are made and these receptor proteins decorate the outer surface of the lymphocytes. The TCRs act as homing devices in that they recognize and bind to certain molecules found on the surface of tumor cells. The TCRs then activate the lymphocytes to destroy the cancer cells.
In this study, newly engineered lymphocytes were infused into 17 patients with advanced metastatic melanoma. There were three groups of patients in this study. The first group consisted of three patients who showed no delay in the progression of their disease. As the study evolved, the researchers improved the treatment of lymphocytes in the lab so that the cells could be administered in their most active growth phase. In the remaining two groups, patients received the improved treatments. Two patients experienced cancer regression, had sustained high levels of genetically altered lymphocytes, and remained disease-free over one year. One month after receiving gene therapy, all patients in the last two groups still had 9 percent to 56 percent of their TCR-expressing lymphocytes. There were no toxic side effects attributed to the genetically modified cells in any patient.
So 2 out of the 14 patients who received better optimized later rounds of therapy are cancer-free over a year later.
This team is trying various ways to enhance the treatment. They are also creating lymphocytes to target breast, lung, and other cancers.
"We are currently treating advanced melanoma patients using adoptive transfer of genetically altered lymphocytes, and we have now expressed other lymphocyte receptors that recognize breast, lung, and other cancers," said Rosenberg.
Developing the new treatment involved first investigating the chemical markers on the outside of cancer cells that the body's natural immune system recognises. The team honed in on chemical markers unique to melanoma cells, such as one called "MART-1".
As more is learned about various types of cancer and as instrumentation for detecting and measuring proteins on the surfaces of cells become more sensitive the scientists will gain more targets on cancer cells to aim immune cells at.
The fact that only two out of the seventeen patients in this trial responded is disappointing, says Davis. The researchers suspect the problem was that their technique did not always alter the T cells in the desired way; they say they have improved their technique in the months since this trial was done, so future remission rates should be higher.
This therapy will only get better. Development of better ways to deliver gene therapy will enhance the effectiveness of this therapy by providing scientists with a way to convert a larger fraction of T cells into cancer killers.
Cancer is curable. Most of us are going to live to see it cured.
Other researchers are working on similar strategies. Hwu, of M.D. Anderson, is engineering lymphocytes that have receptors for substances called chemokines that some tumors put out. This will help the lymphocytes home in on the cancer.
"We need to figure out how to get the T cells to migrate into the tumor more efficiently," he said. "If the T cells are able to recognize the cancer but are circulating in the bloodstream, then they are not on the battlefield where they need to be."
One problem that immunotherapies need to address comes from compounds which some cancer cells secrete that basically discourage immune cells from approaching. These compounds are one reason cancer vaccines have not achieved great success. A combination of immune cells aimed at cancer cells with monoclonal antibodies or other approaches that aim at the immune system damping compounds would be more potent.
An international team of scientists reports that a single 400-milligram daily dose of celecoxib, commonly called Celebrex® and manufactured by Pfizer, significantly reduced recurrence of adenomas, or pre-malignant colon tumors - within three years of previous adenoma removal.
The New England Journal of Medicine today published findings from the Prevention of Spontaneous Adenomatous Polyps (PreSAP) study, involving more than 1,550 participants at 107 sites in 32 countries on six continents. The study was led by Nadir Arber, M.D., chair of the Integrated Cancer Prevention Center and professor of medicine and gastroenterology at the Tel Aviv Sourasky Medical Center and Bernard Levin, M.D., vice president of Cancer Prevention and Population Sciences at The University of Texas M. D. Anderson Cancer Center.
"Celecoxib 400 mg once daily significantly reduced colorectal adenoma occurrence, with a greater effect on advanced adenomas," said Arber.
As excess amounts of the protein cyclooxygenase (COX-2) are associated with adenomas and colon cancer, PreSAP researchers studied celecoxib - a selective COX-2 inhibitor - to prevent the pre-cancerous lesions.
The differences between the placebo and celecoxib groups was substantial.
In the placebo-controlled, double-blind PreSAP trial, study leaders randomly assigned participants to receive either a single 400-mg dose of celecoxib (approximately 930 subjects) or a placebo (nearly 630 subjects). Subjects received colonoscopies after one and three years to detect potential pre-malignant tumors and their sizes, as well the overall adenoma burdens for participants. All polyps were removed and examined by study pathologists.
At the conclusion of the trial, the cumulative adenoma rate for the celecoxib study group was 33.6 percent, while the cumulative rate of adenoma development in the placebo group was 49.3 percent (a 36 percent reduction). Celecoxib administration was associated with a 50 percent reduction in larger, potentially more dangerous adenomas.
"Unlike the recent Adenoma Prevention with Celecoxib (APC) trial, we did not find a statistically significant increase in cardiovascular risk associated with the use of 400 mg of celecoxib once daily," said Levin. "That said, because of the significant cardiac side effects seen in the APC study, further cardiovascular research on the use of all anti-inflammatory drugs, such as Celebrex®, Aleve® and Motrin®, as chemoprevention tools is warranted.
"Low dose aspirin also has been shown to reduce adenoma formation in individuals with a prior history of polyps and has the potential to decrease cardiovascular disease risk," said Levin. "However, its use is associated with an increased risk of upper-gastrointestinal bleeding and stroke."
Drugs have trade-offs. As better methods of detecting risks are developed we'll gain better ways to estimate the risks each of us face. We do not all share the same levels of risk of cancer, stroke, heart disease, and other killers. A person at great risk of colon cancer but low risk of heart disease and stroke would gain far more from celecoxib than someone with the opposite pattern of relative risks.
A couple of other recent papers give a sense of the interest medical researchers have in celecoxib against cancer: Celecoxib and Curcumin Synergistically Inhibit the Growth of Colorectal Cancer Cells and Radiosensitivity Enhancement by Combined Treatment of Celecoxib and Gefitinib on Human Lung Cancer Cells. Celecoxib might also slow the development of prostate cancer. Celecoxib might also be helpful against breast cancer.
Generally, COX-2 works by regulating the production of prostaglandins in cells. In the Mayo study, celecoxib reduced levels of COX-2 protein in mammary tumor cells; the therapy was even more effective in minimizing the amounts of COX-2 dependent prostaglandin E metabolites in mammary tumor cells.
“Celecoxib treatment appears to exert its antiproliferative, antiangiogenic, and pro-apoptotic effects by regulating the prostaglandin pathways,” Mukherjee said. “This leads to the reduction in primary breast tumor mass.”
She noted that in an experiment with a limited number of mice, celecoxib appeared to completely inhibit metastasis of the breast tumor.
A COX-2 inhibitor is not going to cure cancer all by itself. But all the ways that cancer cells differ from regular cells make potential targets for drugs that target those differences. Some cancers will get cured by using multiple drugs to target many differences of cancer cells at once. Celecoxib should be seen as a potential player in multi-drug therapies aimed at hitting cancer cells in many ways at once.
Many types of cancer cells have a surplus of procaspase-3. Procaspase-3 can be converted to caspase-3 which initiates the cell suicide process called apoptosis. However, cancer cells have mutations which prevent the conversion of procaspase-3 to caspase-3. Well, a team of scientists developed a drug called procaspase activating compound one (PAC-1) which converts procaspase-3 to caspase-3 and thereby initiates cell suicide.
CHAMPAIGN, Ill. -- Scientists have found a way to trick cancer cells into committing suicide. The novel technique potentially offers an effective method of providing personalized anti-cancer therapy. Most living cells contain a protein called procaspase-3, which, when activated, changes into the executioner enzyme caspase-3 and initiates programmed cell death, called apoptosis. In cancer cells, however, the signaling pathway to procaspase-3 is broken. As a result, cancer cells escape destruction and grow into tumors.
"We have identified a small, synthetic compound that directly activates procaspase-3 and induces apoptosis," said Paul J. Hergenrother, a professor of chemistry at the University of Illinois at Urbana-Champaign and corresponding author of a paper to be posted online this week ahead of regular publication by the journal Nature Chemical Biology. "By bypassing the broken pathway, we can use the cells' own machinery to destroy themselves."
To find the compound, called procaspase activating compound one (PAC-1), Hergenrother, with colleagues at the U. of I., Seoul National University, and the National Center for Toxicological Research, screened more than 20,000 structurally diverse compounds for the ability to change procaspase-3 into caspase-3.
The treatment works because procaspase-3 is often much more abundant in cancer cells than in healthy cells, says Paul Hergenrother at University of Illinois in Urbana, US, who led the study: “In tissue from 23 colon cancer patients we found that, on average, levels of procaspase-3 are eightfold higher than in healthy cells – sometimes as much as 20-fold higher.”
Healthy cells, such as white blood cells, were found to be significantly less affected by the addition of PAC-1 because they had much lower levels of procaspase-3, so cell-suicide could not be triggered.
When the scientists tested PAC-1 on cancerous and non-cancerous tissue from the same person, the tumour cells were 2,000-fold more sensitive to PAC-1.
"It is now clear that many cancers have elevated concentrations of procaspase-3," wrote Prof Hergenrother in the Nature paper. "Others have heightened or reduced concentrations of procaspase-3 depending on the cancer subtype." He added that a systematic analysis of procaspase-3 concentrations in a variety of cancer types was needed to determine which cancers would be most amenable to treatment with a molecule such as PAC-1.
The continued discovery of differences between cancerous and normal cells will provide more targets for anti-cancer drug development. The continued advance in general understanding of cell metabolism and gene regulation will lead to the discovery of many more enzymes and intra-cellular messengers which will become targets for anti-cancer drug development.
I am very optimistic that most of us will live long enough to witness the total defeat of cancer.
In a step toward personalized medicine, Howard Hughes Medical Institute investigator Brian J. Druker and colleagues have developed a new technique to identify previously unknown genetic mutations that can trigger cancerous growth. By analyzing the proteins – instead of the genes – inside acute myeloid leukemia (AML) cells, the researchers have dramatically reduced the time it takes to zero in on molecular abnormalities that might be vulnerable to specific drug treatments.
The researchers are correct in arguing that this approach could lead to use to identify specific mutations for individual cancers so that cancer treatments can be tailored to the characteristics of each cancer case. But that is not the only value of this approach. They also have hit upon a faster way to find proteins whose mutations can cause or at least contribute to the development of cancer. My guess is the identification of more genes which can mutate to contribute to cancer will be the greater value.
"This approach gives us a way to figure out what's driving the growth of a cancer in an individual patient and ultimately match that patient with the right drug," said Druker, who is based at the Oregon Health & Science University in Portland. Druker's team collaborated on the research, which was published in the July 17, 2006, issue of the journal Cancer Cell, with scientists in the lab of D. Gary Gilliland, an HHMI investigator at Brigham and Women's Hospital, as well as researchers at the Portland VA Medical Center, Cell Signaling Technology, the University of Chicago, and Yale University.
Traditionally, cancer-gene hunters have scanned the genome looking for mutations that trigger out-of-control cell growth. Druker tried this approach, but found it wanting. "We were doing some high-throughput DNA sequencing, and we weren't really finding much," he said.
DNA sequencing is a hard way to look for mutations that drive cancer because cancer cells are genetically very unstable and have large numbers of mutations that are just side effects of the cancer. Also, genomes are very large and they end up sequencing lots of sequences that are not genes or that are not getting expressed even if they are genes.
They decided to instead sequence the peptides that make up proteins. This reduces the sequencing job by orders of magnitude.
Instead, the team added tools from the burgeoning field of proteomics, the study of proteins. "We decided this more functional assay would get us to the disease-causing genes more rapidly," said Druker, who has been studying a group of cell-signaling proteins called tyrosine kinases for 20 years.
Tyrosine kinases play a key role in many cancers. In healthy cells, they help form a chain of signals that prompt normal cell growth and division. Sometimes, though, a tyrosine kinase gets stuck in an "on" position, driving out-of-control cell division and, ultimately, cancer. This potentially devastating kinase activation carries a calling card in the form of a molecule called a phosphate.
"The phosphates signal activated tyrosine kinases," said Druker. "So we decided to use the phosphates as markers."
To find these markers, the team took myeloid leukemia cells and chemically digested them into a mixture of protein snippets called peptides. Next, they extracted all of the peptides carrying extra phosphates and sent them through a mass spectrometer, which precisely measured the weight of each peptide. Sophisticated software then sifted through a massive protein database at the National Library of Medicine, identifying each of the team's peptides as a segment of a specific protein. The analysis showed that many of the peptides came from tyrosine kinases. Scanning this list, Druker picked out five as likely suspects.
Sounds like they used RNA interference (RNAi) to block the candidate genes. So they used a number of fairly new techniques to do this research.
Druker's team then introduced into their leukemia cells five segments of RNA that each shut down one of the candidate kinases. Silencing four of the kinases with RNA did nothing – the cells still grew out of control. But with the fifth, the cells no longer became cancerous.
"That left one gene to sequence. We found that the gene, called JAK3, had a mutation that drives the growth of leukemia cells in mice," said Druker. Analysis of additional patient samples later identified two more mutations in the JAK3 gene.
Thomas Mercher, a postdoctoral fellow in Gilliland's lab, then tested the mutation in a mouse model. "It was important to show that the JAK3 mutation, when introduced in mice, would lead to a leukemia-like illness. It did, confirming that the JAK3 mutations play a central role in leukemia," said Gilliland.
One of the reasons I'm optimistic that cancer will be cured within 10 to 20 years is that cancer researchers have such better tools for doing their work as compared to 10 years ago or even 5 years ago. Also, their tools will get better next year and the year after that and enormously better 15 or 20 years from now. Researchers will be able to identify mutations, introduce mutations, interfere function, sequence DNA, sequence peptides, and do other tasks with biological systems more cheaply and rapidly in the future with microfluidics and other advances in techniques. Experiments that are not even possible to do today will become possible and then increasingly easy to do.
An engineered virus tracks down and infects the most common and deadly form of brain cancer and then kills tumor cells by forcing them to devour themselves, researchers at The University of Texas M. D. Anderson Cancer Center report this week in the Journal of the National Cancer Institute.
The modified adenovirus homed in on malignant glioma cells in mice and induced enough self-cannibalization among the cancer cells - a process called autophagy - to reduce tumor size and extend survival, says senior author Seiji Kondo, M.D., Ph.D., associate professor in the Department of Neurosurgery at M. D. Anderson.
"This virus uses telomerase, an enzyme found in 80 percent of brain tumors, as a target," Kondo says. "Once the virus enters the cell, it needs telomerase to replicate. Normal brain tissue does not have telomerase, so this virus replicates only in cancer cells."
Other cancers are telomerase-positive, and the researchers showed in lab experiments that the virus kills human prostate and human cervical cancer cells while sparing normal tissue.
Note that the viruses used in this experiment really are a form of gene therapy. The virus coating delivers a genetic payload into cells. The genes have been arranged to activate only in cancer cells.
I expect we will see two major categories of cancer cures using gene therapy. First, gene therapies will selectively activate and kill only cancer cells. The genes will be engineered to operate only in conditions that are found only in cancer cells or rarely in non-cancer cells. Second, other gene therapies will repair the mutated genes in cancer cells that are causing the cells to divide out of control.
A cancer cell is like a self-modifying computer program that has accidentally changed itself to malfunction in a very dangerous way. We need to either fix the program by sending in program parts to replace the damaged parts or we need to send in another program that only activates and kills when it finds itself inside a cell that is out of control. Gene therapy strikes me as the best solution to cancer because it can be far more exact than toxic drugs.
The idea that aberrations in the number or structure of chromosomes can spur tumor formation is more than a century old. Such aberrations--known collectively as "aneuploidy"--arise in two principal ways: as a consequence of abnormal cell division, or as a result of cell fusion. By either mechanism, the resulting aneuploid cells no longer have the proper genetic makeup and frequently die. But researchers now know that tumor cells are often aneuploid--and very much alive. Whether aneuploidy is a cause or a consequence of a cancerous cellular state is the crux of a current debate.
In a recent study, Dr. Yuri Lazebnik and his colleagues at Cold Spring Harbor Laboratory observed, fortuitously, that normal cultured human cells are fused by the action of the Mason-Pfizer Monkey Virus (MPMV), but that the resulting hybrid cells do indeed fail to proliferate. However, the researchers discovered that if one of the fusion partners carried a particular "predisposing" gene mutation (in the oncogenes E1A or Myc, or in the tumor suppressor gene p53), then a significant proportion of the resulting hybrid cells were highly proliferative and thus potentially cancerous.
The missing piece of the puzzle is the question of whether this phenomenon happens in vivo in human bodies.
Whether such proliferating hybrid cells are produced by viruses in the human body, whether they can lead to cancer, and which of the many known and candidate human fusogenic viruses (for example, endogenous retroviruses, whose DNA sequences comprise at least 8 percent of the human genome) might contribute to cancer remain to be determined.
If this result is demonstrated to happen in the body then that will suggest a much larger role for viruses in cancer development.
I'm increasingly convinced we underestimate the size of the benefits that would flow from the development of a wider range of vaccines against viruses and bacteria that rarely kill people. First off, of course getting cold or flu or a stomach virus is unpleasant and also costs time. But also, both the infections and the body's reactions to infections are probably accelerating the aging process. We could reduce the rate of aging by reducing our total lifetime disease load. We might also reduce our risks of cancer.
Johns Hopkins University scientists led by urology professor Robert H. Getzenberg have developed a more accurate test for prostate cancer using a protein called Early Prostate Cancer Antigen (EPCA).
In the first clinical study of a new blood protein associated with prostate cancer, researchers have found that the marker, called EPCA or early prostate cancer antigen, can successfully detect prostate cancer in its earliest stages.
Greater sensitivity of cancer tests allows for earlier diagnosis and treatment and therefore better outcomes. Also, greater test sensitivity enables more rapid testing of anti-cancer drugs and of dietary and other interventions designed to prevent cancer in the first place.
The new test is much more accurate than the existing Prostate Specific Antigen (PSA) test.
The researchers found that EPCA levels were high in 11 of 12 prostate cancer patients (92 percent) and low in all the healthy individuals. Only two bladder cancer patients and none of the other patients had elevated EPCA levels, suggesting that for this study, the test was correct 94 percent of the time. In comparison, only one-quarter of patients who undergo biopsies because they have elevated PSA values are actually positive for prostate cancer, while as many as 15 percent of those with low PSA values were found to have prostate cancer as detected by biopsy, according to Getzenberg.
Larger clinical trials are under way to further refine the EPCA test, to make it more sensitive so it can pick up even the smallest traces of the marker and to verify its usefulness for detecting prostate cancer in a larger sample of patients, Getzenberg said.
Earlier cancer diagnosis will produce an unintended and yet ultimately beneficial consequence: The total number of people walking around with known cancer will rise dramatically. Therefore more people will feel the urgent need to support cancer research. A person who gets a cancer diagnosis and is told they have 6 months to live has little incentive to support cancer research and little time in which to do so. But a person who gets a cancer diagnosis 5 or 10 years before the cancer is going to reach the terminal stage has a lot of time and energy to devote to supporting cancer research.
This same phenomenon of increasingly earlier diagnosis years before a disease kills its sufferers is being repeated across many other types of diseases. Scanning technologies such as MRI, new blood tests, saliva tests, and other tests are leading to increasingly earlier diagnoses. In some cases this allows earlier and more successful treatment. But for incurable disorders this trend is also producing a growing body of people who now live for years knowing they have a fatal disease. This focuses more minds in support of developing better treatments.
Normally if a cancer cell line is injected into a mouse the cancer cells grow. Some scientists at Wake Forest University discovered a mouse that was immune to injected cancer and have bred it and produced many generations of cancer-proof mice.
A cancer-proof mouse, which can survive being injected with any number of cancer cells, has been discovered by US scientists. The discovery of the resistant mouse could pave the way for future gene or drug therapies if the mechanism by which it fights cancer can be understood
This is amazing for a few different reasons. First, it is amazing that it is possible at all. An immune system that can kill such a large variety of types of cancer which does not appear to cause auto-immune disorders is not something I would have expected to be possible. Cancer cells look too much like normal cells and most cancers (perhaps virally caused cancers are an exception) are probably expressing only genes that naturally are expressed in human cells. So where does the specificity come from that lets an immune system knock out a large variety of cancers? Just figuring it out will reveal very useful knowledge.
What is also amazing about it is that the mutation happened and someone noticed. It is hard to say what the odds are for the occurrence of a mutant that would have the resistance to cancer.until it is discovered how the mechanism works and how many mutations had to happen for a mouse to have cancer resistance. Still, it seems amazing to me.
Here are more details.
WINSTON-SALEM, N.C. – Scientists at the Comprehensive Cancer Center of Wake Forest University have developed a colony of mice that successfully fight off virulent transplanted cancers.
"The mice are healthy, cancer-free and have a normal life span," the 10-member team reported in the Proceedings of the National Academy of Sciences online edition to be published the week of April 28.
The transplantation of the cancer cells in these special mice provokes a massive infiltration of white blood cells that destroy the cancer, said Zheng Cui, M.D., Ph.D., associate professor of pathology at Wake Forest University Baptist Medical Center and the lead scientist
"The destruction of cancer cells by these leukocytes is rapid and specific without apparent damage to normal cells," Cui said. "These observations suggest a previously unrecognized mechanism by which the body can fight off cancer."
The discovery of a genetic protection from cancer in mice "may have potential for better therapy or prevention of cancer in people," the team said. It also could help explain why some people are protected against cancer despite prolonged and intense exposure to carcinogens..
The discovery also could help solve another mystery. For years, scientists have been searching for the mechanism that permits spontaneous regression of human cancers without treatment. Cui said these cases are well-documented, but occur rarely. The new mouse colony gives the team the opportunity to study the mechanism in an animal model.
Cui and his colleagues began the mouse colony almost by serendipity. As part of ongoing cancer studies, they were injecting a virulent type of cancer cell that forms highly aggressive cancers in all strains of laboratory mice and rats. When injected into the abdomen, the tumor grows exponentially, causing the abdomen to fill with fluid within two weeks. The cancer can then progress by metastasizing into the liver, kidney, pancreas, lung, stomach and intestine.
But, said Cui, one male mouse unexpectedly remained free of the cancer despite repeated injections. The Wake Forest team was able to show this was genetic and to develop a colony from that single mouse. The colony, now about 700 mice, remains exclusively at Wake Forest. Meantime, the original mouse "remained healthy, cancer-free and eventually died of old age after a normal lifespan."
When the cancer-resistant mice were bred with normal partners, the researchers found that about half of their offspring were resistant to cancer cells, indicating that this genetic protection is dominant and is likely due to a change in one gene. The resistance continued in future generations.
Depending on the age of the mouse, some had complete resistance -- the cancer never got started -- while others displayed spontaneous regression -- the cancer started developing over a period of a couple of weeks, but then it rapidly disappeared in less than 24 hours.
"The mice became healthy and immediately resumed normal activities including mating," Cui said. They tested them again with another injection of the cancer cells. He said that once the mice developed the protection, they never again developed the cancer.
The researchers said the mouse model "represents a unique opportunity to examine cancer/host interactions."
Cui said the new mouse model also may help in solving another medical mystery -- why cancer becomes more common when people age. The usual explanation is that mutations accumulate in the body, leading to precancerous conditions that eventually become cancer.
But, he said, the mouse model suggests that the body's natural protection -- which scientists call host resistance -- declines with age.
Note that this result suggests another reason why the aging of the immune system is a significant problem. Luckily, it will probably be easier to develop rejuvenating cell therapy treatments for the immune system (also see this post) than for many other systems of the body.
How would a mutation that is found in a laboratory mouse strain be usable to create an anti-cancer therapy for humans? Well, the human and mouse genomes have both been sequenced and they have corresponding sections that can be lined up for 90% of their regions. Once the mutation location(s) responsible for this are found in mice then it is likely there will be a corresponding regions in the human genome. It may be possible to introduce equivalent mutations into the DNA of human leucocyte stem cell lines using gene therapy and then inject those stem cells into humans suffering from cancer. Then the cells would multiply and turn into immune cells that fight cancer. Many parts of the transfer of blood stem cells between humans is routinely done as part of leukemia treatments and for other disease treatments..
This mutation (or set of mutations - the capability may the result of a combination of mutations) is likely to have previously occurred in the wild. The fact that the mutation does not normally occur in wild type mice or naturally in other mammalian species suggests that either protection against cancer was not selected for by evolution because other things were killing mammals first or that the mutation has some cost in terms of reproductive fitness. It will be interesting to see how that shakes out.
Even if the mutation turns out to have some downsides it might still be useful as part of a therapeutic treatment. After all, when the downside of not getting treated is death then the side-effects (whatever they might be) of a revved up immune system may be worth it. Also, it might even be possible to add the mutation in a way that can be turned on and off. Attach the relevant gene to a regulatory region that can be switched on and off by a drug. Then even if there was a side-effect to this capability in the immune system it could be activated only long enough to wipe out a cancer.
Another thing that is great about this discovery is that it provides a model to figure out. Here's an immune system that can wipe out a large assortment of cancers. How? The detective work that will be done to figure that out will yield information that is useful by itself. It is even possible that the discovery of the knowledge of how these mice attack cancer will point the way to how to train an immune system to fight cancer with a method less drastic than gene therapy. Perhaps a vaccine could be developed that would train a human immune system to do the same.