July 11, 2012
Cancer Evolves: Why It Keeps Beating New Therapies
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.
Whatever suite of sequential or concurrent therapies that is developed, it must be tailored to the particular patient's genome.
Epigenomic and immunological tuning would be helpful, too.
Acute promyelocytic leukemia, a fairly uncommon disease, is a good example of how a particular drug (all-trans retinoic acid, ATRA) can be used to induce cancer cell to differentiate in a favorable direction:
The basis for current treatment programs for APL is the sensitivity of leukemia cells from patients with APL to the differentiation-inducing effects of ATRA. The dramatic efficacy of ATRA against APL results from the ability of pharmacologic doses of ATRA to overcome the repression of signaling caused by the PML/RARA fusion protein at physiologic ATRA concentrations. Restoration of signaling leads to differentiation of APL cells and then to postmaturation apoptosis. Most patients with APL achieve a complete remission (CR) when treated with ATRA, though single-agent ATRA is generally not curative.[21,22] A series of randomized clinical trials has defined the benefit of combining ATRA with chemotherapy during induction therapy and also the utility of using ATRA as maintenance therapy.[23-25] ATRA is also commonly used as a component of postinduction consolidation therapy, with treatment regimens that include several additional courses of ATRA given with an anthracycline with or without cytarabine.[10,13,14,26] Evidence for the benefit of giving ATRA with consolidation chemotherapy is derived from historical comparisons of results from adult APL clinical trials showing significant improvements in outcome for patients receiving ATRA given in conjunction with chemotherapy compared with chemotherapy alone.[13,14] For children with APL, survival rates exceeding 80% are now achievable using treatment programs that prescribe the rapid initiation of ATRA and appropriate supportive care measures.[1,8-10,13,14,26]
Funnily enough, I seem to recall that Michael Behe, the great ID bugbear, dealing with this very topic at length in The Edge of Evolution, though he focused much more on malaria than cancer.
RE: In a Rather 'Horrible' Way.....
....it's interesting to see the AMA and Pharmas jumping all over the place trying to find a cure for this dread disorder....
.....when the cure was discovered back in 1997 by researchers at Princeton. The reason it wasn't shouted to the world because you can't patent—and make a billion dollars—off of a naturally occurring substance: graviola, from South America, and pawpaw from North America.
I say the pawpaw kill an aggressive squamous carcinoma in a month. Graviola beats down the squamous carcinomas I get, occassionally.
Yet the information is suppressed....can't 'imagine' why.....
P.S. In the meantime, over 500,000 Americans die of this horrible ailment.....and the AMA and Pharmcos keep raking in the money......go fig.....
"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."
so basically, they get to tell a patient(and funding) that their theory worked, but the cancer cheated and adapted, and the end result is that it didn't work. but...with a little more money...
on the hypothetical acceptance that the therapy did work, initially, whose to say that the body didn't simply developed a method of resistance to their treatment, proliferating the wbcs that would aid in the elimination of the foreign body(their drug)?
The patient's genome is of less interest than the mutations in the cancer. We need to drive those mutations with toxins to set up a sort of metabolic house of cards in the cancer cells.
I'm not arguing for differentiation in a direction. I'm arguing for evolution in a direction. Select for mutations that drive the surviving cancer cells into a state where they become very vulnerable.
One obvious approach is to make them up-regulate enzymes way above what normal cells would ever express them. Then use those enzymes to convert non-toxins into toxins. Another approach: Use attacks against that cause them to express proteins that show up on their cell surfaces (e.g. transport proteins that expel harmful compounds). Then hit them with a mono-clonal antibody attack against those surface proteins.
I wonder if the 'random' mutation framework of understanding doesn't work against a cure? We see bacteria adapt when stressed to unleash mutations in a restricted subrange of genetic material, to metabolize nylonase, for instance. It seems if the process by which mutations are initiated is targeted, perhaps the resistance would be neutralized. Better yet, if a telic framework is correct, the cure may lie in understanding a genetic code that is adaptive and prescriptive because it IS a code, not a lucky happenstance of time+chance+environment.
We should really stop using painful debilitating poisons that harm the cancer slightly more than the patient, and instead focus on developing treatments that narrowly target the affected genes that make cancer cells cancerous. Unfortunately, incrementalism seems to be the rule.
"focus on developing treatments that narrowly target the affected genes that make cancer cells cancerous."
Sadly, the problem is usually the destruction or malformation of genes which suppress cell division, not the acquisition of new ones.(ie, it still retains all the "markers" of being just another host cell, though the runaway mutation rate will eventually mess up those markers and clue in the immune system to the problem, though by then it's usually too late.) The best defense against cancer is early isolation and removal, not attempting to fight it after it spreads all over the body eating up resources and hiding in its various nooks and crannies.
But even after the defeat of the cancer of the moment, the fact is that a lot of cancers are highly predictable from common mutations in common cells. The danger is inherent in the powereful forces present in the system; the fact that a system that depends on controlled reproduction CAN control it to accomplish its purposes is the amazing thing.
The fight against cancer is the fight against the inevitable entropy of a not-so-closed system, and if your system is already deteriorating, any of your other cells from anywhere else in your body might be the next to rebel from sheer mutational inertia. At some point you have to count the cost to your future of expensively delaying a problem universal in all living things.
Learn what you want now and do it, then focus on producing and training the next generation in the basics. A life as a selfish gene instead of a productive cell is not a life well spent.