For all the weapons deployed in the war on cancer, from chemicals to radiation to nanotechnology, the underlying strategy has remained the same: Detect and destroy, with no compromise given to the killer. But Robert Gatenby wants to strike a peace.
A mathematical oncologist at the Moffitt Cancer Center, Gatenby is part of a new generation of researchers who conceive of cancer as a dynamic, evolutionary system. According to his models, trying to wipe cancer out altogether actually makes it stronger by helping drug-resistant cells flourish. Rather than fighting cancer by trying to eradicate its every last cell, he suggests doctors might fare better by intentionally keeping tumors in a long-term stalemate.
It’s an unorthodox notion. But nearly 40 years after Richard Nixon declared war on cancer, orthodox approaches have produced little in the way of treatment. Cancer death rates have fallen by 20 percent in the last 15 years, but experts say that much of the improvement comes from lifestyle changes, especially drops in smoking, and early detection. Most new cancer drugs provide just a few extra weeks or months of life — a welcome delay, but all too brief.
“It’s hard to convince doctors or patients not to give the maximum dose of chemotherapy and kill as many cells as possible, because that seems like the right thing to do. But the models suggest that it’s the wrong thing to do,” said Gatenby. “The models suggests that we have to go against what’s intuitive.”
Gatenby’s models of long-term cancer stability are scheduled to be published next week in Cancer Research, and he describes his approach in an essay published Wednesday in Nature. He spoke to to Wired.com about a different approach to cancer.
Wired.com: Where do we stand now in the war on cancer?
Robert Gatenby: We’ve learned enormous amounts about the disease, but it hasn’t translated into therapy. My proposal isn’t necessarily right, but it’s an alternative way of thinking.
We’re coming at cancer with a paradigm in the tradition of Paul Ehrlich and magic bullets, which was successful in treating bacterial infections in the mid-20th century. The conscious or unconscious analogy is that we’d like to find antibiotics in cancer. We’d like to find a cure.
Wired.com: Are the dynamics of fighting cancer so very different than fighting bacteria?
Gatenby: Bacterial cells are so fundamentally different than our normal mammalian cells. Finding something that works on bacteria, but not our own cells, is much easier than finding something that distinguishes between normal and non-normal cells.
Bacteria also tend to be exquisitely sensitive to antibiotics. They develop resistance, but that occurs over a long period of time. The sensitivity of tumor cells to therapy is nowhere near as great, and they’re much more heterogeneous. You have resistant phenotypes present before you even start treatment.
Wired.com: In your article, you say that drug-resistant cancer cells are actually less reproductively fit than non-resistant cells. Why doesn’t killing off the non-resistant cells leave behind a weaker population?
Gatenby: Being drug-resistant costs cells energy. Even when you’re not giving a drug, cells are still using energy to maintain their resistance mechanisms. So drug-resistant cells don’t have that energy available for proliferation. They’re not as fit as the drug-sensitive cells, and are only present in small numbers.
That balance completely changes when you give high-dose therapy. What you’ve done then is kill their drug-sensitive competitors, and left the field open to drug-resistant cells.
Wired.com: What’s the alternative?
Gatenby: How people treat invasive species can provide an analogy for thinking about cancer therapy. In treating a field for a pest, for example, you might treat three-quarters of it with a pesticide, and leave the other quarter untreated. Pesticide-sensitive pests remain there, and they spread out into the field after treatment, preventing pesticide resistance from becoming dominant.
Using pesticides on an entire field is like what we’re doing with cancer now. And we all agree that we’d rather get rid of the pests altogether, but if you can’t do it, if every time you have an infestation you treat it and get resistance, then you try a different strategy. The alternative is to try to reduce the pest population so that it doesn’t damage your crop, and accept the fact that they’re going to be there. That’s what I’m talking about with cancer.
Wired.com: What type of treatment would that involve?
Gatenby: Instead of fixing the dose of the drugs, you fix the size of the tumor. Your whole goal is to keep the tumor stable. You continuously alter the drug, the dose, the timing of the dose, with that goal in mind.
Wired.com: Outside of your mathematical models, is there evidence to suggest that this might work?
Gatenby: With a mouse ovarian cancer model, if you treat it with a very high dose, the tumor goes away. It looks like you’ve cured it. But a couple weeks later it comes back and starts killing animals. This is a standard outcome.
What we did is use smaller doses of drugs and applied them when necessary. We were able to keep tumors stable and mice alive indefinitely.
Wired.com: So we don’t need new drugs, just different ways of applying them?
Gatenby: Of course we need to keep looking for new drugs and more effective therapies. But the lesson we can learn is that the judicious use of drugs can be more effective than the intuitive approach of killing as much as you can.
Citation: A change of strategy in the war on cancer. By Robert Gatenby. Nature, Vol. 459 No. 7246, May 27, 2009.
Image: WikiMedia Commons
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