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Moffitt researchers use game theory to rethink cancer treatment.

It sounds like the premise of a wonky video game: a high-stakes contest between predators in white coats and the cancer cells that are preying upon their patients.

Oncologists probably don’t see themselves in the “predator” role. Perhaps they should and, while they’re at it, take their cues from the branch of mathematics devoted to analyzing strategies in competitive situations. It’s called game theory. Researchers from Moffitt Cancer Center and Maastricht University argue that cancer treatment approaches shaped by game theory can improve on the current standard of care, providing better odds for victory measured in lives saved or prolonged.

Their review article recently published in the journal JAMA Oncology reframes cancer treatment as a game of predator (physician) versus prey (a patient’s cancer cells). Physicians hold two advantages in this high-stakes game:

  • Physicians always make the first move. Cancer cells respond either by dying or developing some sort of resistance — but only after they’re exposed to the treatment.
  • Physicians can anticipate, while cancer cells can only react. Cancer cells don’t think. They respond to whatever treatment is thrown at them. Physicians, on the other hand, can plan a strategy based on their understanding of the patient’s cancer and principles of evolution — one that leads toward better patient outcomes.


Both advantages disappear under the current approach to treatment. By repeatedly hammering the cancer cells with the same chemotherapy drugs at the maximum dose a patient can tolerate, those cells are offered multiple unopposed opportunities to develop resistance. And that leaves physicians reacting rather than anticipating and shaping the course of the disease.

Dr. Robert Gatenby, co-director of Moffitt’s Center of Excellence in Evolutionary Therapy and the article’s other researchers compare it to a rock-paper-scissors game “in which the vast majority of cells within the cancer play, for example, ‘paper.’ It is clearly advantageous for the treating physician to play ‘scissors.’ Yet, if the physician only plays ‘scissors,’ the cancer cells can evolve to the unbeatable resistance strategy of ‘rock.’”

So, what does game theory suggest about better strategies against cancer? It depends on whether the physician’s goal is to cure the cancer or, when that’s not possible, to prolong life.

Robert Gatenby in collaboratorium

Dr. Robert Gatenby, a mathematical oncologist and the study’s corresponding author, has been studying the evolutionary dynamics of cancer for many years and is an acknowledged leader in the field.

Sucker’s Gambit

While a cure may be possible in some cancers, it’s rarely achievable in the first blunt-force attack of maximum tolerated dose chemotherapy. Instead, the researchers suggest a strategic sequence of treatments. Initial therapy could be designed to kill off all but a small subpopulation of cancer cells, which can be killed by a second treatment targeting the adaptations that allowed those remaining cancer cells to survive the first drug. In effect, the sucker’s gambit has the physician shape the evolution of cancer resistance to yield a subset of surviving cells that are easy to kill with targeted therapy.

Tipping Cancer’s Hand

When a cure is not achievable, the goal becomes maximizing the patient’s time to progression of their disease. Precision medicine has been a boon to physicians in that it can look at a patient’s genetics on a molecular level to predict how they might respond to a given drug before it’s even administered. But more needs to be learned about the molecular factors within a patient’s cancer that might increase its ability to resist a given chemo drug.

In the meantime, physicians might learn more about potential resistance by probing the cancer with short bursts of different drugs in smaller doses to see how the cells respond. From here, the physician could strategize a series of drugs that pick off each subpopulation of cancer cells, one by one — and thus prolong survival.

For many patients, that would be a big win.