May 04, 2006
Genetically Engineered Viruses Selectively Kill Cancer Cells
A genetically engineered virus selectively kills cancer cells.
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.
While a great advance, what happens if this stuff also goes to roost in stem cells, which have high levels of telomerase expression?
Do I wipe out the tumor and take 20 years off the patients life from stem cell depletion?
Might still be an advantage if my glioma is going to take me in 18 months flat...
This is a valuable advance in cancer treatment ideas and the researchers should be congratulated. However, it is possible to think of negative complications that I hope can be avoided. For example, telomerase is also expressed in non-cancerous cells that are important to bodily health and reproduction. Consider this excerpt from a web page at the Institute of Genetics at the University at the University of Leicester :
Telomerase is active in the human germline and in some stem cells but inactive in differentiated somatic cells, consequently telomere length declines in most tissues as we age. The regulation of telomere length plays a role in cellular senescence and in cancer. Most cancer cells are immortal and they are able to maintain telomere length either via the enzyme, Telomerase, (approximately 90% of tumours) or by an another pathway known as ALT (Alternative Lengthening of Telomeres). The ALT pathway is poorly understood although some tumours are ALT+ and novel anti-cancer therapies, targeted against telomerase, may select for ALT+ cancer cells.
A virus that selectively knocks out cells that have active telomerase might knock out germline cells and this might cause sterility Also, this virus type might knock out stem cells that are needed for bodily maintenance and the replenishment of aging cells (Rsilvetz also mentions this problem above). Of course, some cancer treatments currently in use cause sterility and patients typically prefer this side-effect to death. Also, it is possible to donate and preserve sperm or eggs before treatment commences.
The quote above suggests another complication. If some of the cells in the tumor utilize another pathway known as ALT (Alternative Lengthening of Telomeres) then when the virus is applied those cells would be selected for differential survival. The tumor might continue to grow even if it initially shrinks. However, I do not wish to be negative. It is great work. Maybe the adenovirus virus can be chosen so that it will not infect germline cells or stem cells.
Perhaps because of my ignorance, why can't this viral approach be followed up with stem cell therapy (which is also advancing along nicely)?
Sure we knock down stem cells while killing the cancer (seems kinda like chemo in that regard - gotta hurt to heal), but after the virus runs its course, we reintroduce the stem cells as needed (presumably your own drawn from your body pre-therapy and screened for cancer).
Jody, good question. The following example "torn from the headlines" may give a sense of the complexity of the proposal you offer. Which doesn't mean it isn't a good idea--it is.
It's been clear for some time that, for breast cancer, chemotherapy following surgery and radiation is effective in increasing survival rates. Current chemo increases the rate of non-recurrence by about one-third. (e.g. consider two cohorts of 100 patients, each with a similarly-staged breast cancer. Cohort #1 gets surgery and radiation; over the next 10 years, 30 of the 100 individuals suffer a recurrence. Cohort #2 gets the same surgery and radiation, followed by chemotherapy. Over the next decade, 20 of the 100 individuals would suffer a recurrence--a reduction of one-third.)
In the 1990s, clinicians made a logical deduction. Since chemo works by killing cancer cells remaining after radiation and surgery, higher doses of chemo should kill more of them, improving survival. The problem was always that the maximum dose was constrained by the fact that chemo also killed stem cells, specifically hematopoietic stem cells (HSCs) resident in the bone marrow. With the advent of HSC therapy successes for some leukemias, the opportunity arose to transfer this technology to benefit breast cancer patients. The idea was to increase chemo to dose so high that it would be lethal, and then reconstitute the patient's HSCs with an HSC transplant.
Because the thinking behind this idea was so clear, there were major clinical trials for this approach in the US and Europe. The results in the early 2000's were pretty clear: high dose chemotherapy confers no survival advantage on breast cancer patients. This therapy is no longer in favor.
I haven't dug up any links, but this precis ought to give you enough information to find good ones at NCI, etc.
The point is that one of the major delays in bringing therapies to the clinic is that each has to be subjected to the tests of "evidence-based medicine," which usually means lengthy and expensive clinical trials with large numbers of patients. The fact that an idea for a therapy is good, innovative, and logical does not mean that it will work in practice. If it does look safer and more effective than the alternatives, the patient population that would benefit still has to be defined.
Yes, I wondered about the toxicity of this treatment toward stem cells. I wonder if stem cells express telomerase but rarely. Think about it intuitively. They could build up their telomeres in several hours or days and then not need to build them up again for months or years. So I expect limited toxicity toward stem cells for this treatment and less toxicity than the chemotherapy agents cause.
Also, I see the use of telomerase as the activating agent as a first cut approximation. The development of more complicated triggering rules that use the activation state of more genes will eventually supercede this first cut attempt at selective toxicity toward cancer cells.
I see cancer cells as DNA programs (like software programs) that have a number of corruptions in their regulatory system. It will certainly be possible to work out fancier gene therapy DNA programs that will use more discriminating rules for what constitutes a cancer cell.
I'd go even further: I want to have my old aged stem cells some day wiped out entirely and replaced by youthful stem cells. The old mutated stem cells at best take up room better used hy younger stem cells while not providing much benefit. At worst they become cancers (a substantial fraction of all cancers start out as stem cell mutations) or spew free radicals or incorrectly create compounds that send wrong messages to other cells or cause still other mischief.
So, yes, stem cell therapy will some day replace stem cells lost to cancer treatments. But we may opt to wipe out stem cells without yet having cancer in the first place.
Good point about replacing older stem cells Randall.
--I am still betting on nanotech to be the way for treating cancer.. but like I see in automobile technology.. even things I'd nearly written off, bounce back into making sense with a surprising breakthrough.
There is an interesting example of stem cells in one part of the body being replaced with some very youthful stem cells in a New York Times article entitled A Painless Donation, an Enduring Lifeline. The fun wrinkle in the story is the sex switch. Here is an excerpt:
Ten years ago Stephen Sprague of New York had the same disease (chronic myelogenous leukemia) as Mr. Mark but at a time when there were no drugs to keep him going. He had no relative who could help, and there was no match for him among the millions of potential donors in the National Marrow Donor Registry. On the verge of death, he was saved by a transplant of umbilical cord cells from a newborn girl, whose cell type proved to be a perfect match for him. "Somewhere on the streets of New York there's an 8-year-old girl who has absolutely no idea what she's done for me," said Mr. Sprague, 58, all of whose blood cells are now female.
This phenomenon might allow for a fine plot twist in a television program such as CSI (Crime Scene Investigation).
Stem cells have been implicated in many forms of cancer from leukemia to solid tumour cancers like those of the breast, prostate and brain. They are in fact cancer stem cells. Possibly, adult tissue stem cells with the right mutations leading to the disease.
Given the compelling and rapidly increasing evidence that cancer might very well be a STEM CELL disease then I am going to predict that treatments that have the ability to selectively destroy Stem Cells be it viral, nano or any other type of delivery system will be the ones that will effect a cure.
Cancer stem cells can remain dormant, only dividing rarely thus are impervious to the cytotoxans.
The rapidly dividing cancer cells that form tumours will not survive without a cancer Stem Cell that produces them.
CANCER SEEMS NOT TO BE A DESEASE BUT RATHER PROGRAMING ERROR IN OUR STEM CELL GENO.
THEREFOR BOMBARDING CANCER WITH CHEMOTHERAPY OR RADIATION IS USLESS.
A METHOD OF REPROGRAMING STEM CELLS SEEMS TO BE THE ONLY SOLUTION.
I BELIEVE NANO TECHNOLOGY TO BE THE KEY TO REPROGRAMING STEM CELL BEHAVIOR.
THE PROCESS WOULD BE ONE OF DEVELOPING NANO ANTI VIRUSES WHICH KILL OF STEM CELLS CREATING CANCER.