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Using Game Theory to Treat, and Beat, Cancer



Imagine the human body as if it were a three-dimensional game board, its "squares" (or cubes, rather) so small as to be invisible to the naked eye – a couple of hundred, or perhaps a few thousand, cubic micrometrical dimensions. These are the dimensions of most human cells.

Now imagine that a brutal game is played on this 3D table. Player one is cancer. He makes the first move. And it takes more and more squares until Player Two – the body's immune system – recognizes the threat and starts counterattacking. Soon, however, the malicious part escapes the defenders and gains ground again. The cancerous tumor grows bigger until, in the end, it occupies so much of the gaming table that you (the guest of this unfortunate game) can not help but notice and nervously go to the doctor.

This is the first game: the cancer is born furtively in the body.

But now begins a second. And here, in theory, the rules change: Player One, this time, is the oncologist, and she or he often starts the game by attacking the cancer with massive doses of cytotoxic drugs. The goal, in this case, is to wipe out Player Two before it can recover and start spreading again.

Sometimes, this simple club of a strategy works. But often, too often, unfortunately, this is not the case. Malignant cells resistant to initial therapy survive and then repopulate; in a short time these rebels tempered by the battle spread to distant parts of the body. This is called metastasis and once the process has begun, it is very difficult to stop. Player two wins.

This year, the American Cancer Society estimates that this rotten scenario will play 609,640 times only in the United States.

But if I could change the game? This, in fact, is the proposal of an extraordinary document, entitled "Optimization of the treatment of cancer using game theory", which was published in the journal JAMA Oncology yesterday. The review article, by Kateřina Staňková from the University of Maastricht in the Netherlands, and Joel S. Brown, William S. Dalton, and Robert A. Gatenby from the Moffitt Cancer Center in Tampa, Florida, a well-argued case to overturn the way we treat most tumors today. Rather than attempting to eliminate the disease in the first move, such as researchers, we should force these rapidly evolving cells to reveal their treatment pathways ahead of time and then systematically block them each.

The "game" of cancer treatment (as opposed to the development of cancer itself) has two inherent asymmetries, say the authors: the first is that there is only one "rational" player, the oncologist. Cancer cells do not think or anticipate or plan a strategy ahead of time; They adapt to. The second is that, in this game, the doctor makes the first move. He or she offers some sort of therapy to the patient and then the tumor cells respond to it ̵

1; either dying or evolving (developing resistance to treatment). Here, the doctor is the leader and the cancer is the follower; or to frame it in another way, it is a competition between predator (the doctor) and prey (cancer).

But too often, as noted above, the oncologist renounces both of these benefits by giving a single high-dose therapy or pharmacological regimen for a fixed period of time, switching only therapies after tumors they start to grow again:

"By repeatedly administering the same drug (s) to the progression of the disease," explain Gatenby and colleagues, "the doctor" plays "a fixed strategy even while the opposite cancer cells continuously evolve successful adaptive responses In addition, by changing treatment only when the tumor progresses, the doctor cedes the leadership to the tumor cells and treatment failure becomes almost inevitable. "

Cancer, in other words, becomes the leader and the doctor becomes the follower.

Or think of cancer therapy as a game of "paper-rock scissors" -yes, this is their analogy, not mine.

"If almost all the cells inside the cancer play, for example," paper "[it] it is clearly advantageous for the attending physician to play" scissors. "However, if the doctor only sounds "scissors", the cancer cells can evolve towards the unbeatable "rock" resistance strategy.

the traditional approach could produce a short-term success (reduction of the tumor or even a complete temporary remission), "but the lack of anticipation of the long-term evolutionary arc allows the tumor to evolve resistance without opposition," write the researchers

solution: an answer could be to try to "driving cancer" through what they call "therapy probes", ie administering smaller doses of different drugs in shorter periods of time to fine-tune the various responses of cancer cells. (What mechanisms of resistance do they evolve, for example, when an X or Y drug is administered?) The next step is to use this information to address each of the surviving subpopulations, always with therapeutic scalpels, not with mallets.

The strategy would have been almost impossible to make it a generation ago. But modern tools of precision medicine – which make it much easier to identify cancer cell populations with their molecular signatures – have made the approach practicable.

Gatenby, a mathematical oncologist and correspondent author of the study, has studied the evolutionary dynamics of cancer for many years and is a recognized leader in the field. He and his colleagues also do not seem to have run out of analogies:

"Consider an eager dog chasing a squirrel by running directly on it," they write. "The coyotes, on the contrary, have learned that the squirrels respond to the pursuit by running to the nearest tree and, therefore, do the same.In the first fight, the squirrel becomes the leader while the dog follows him in a wide arc towards and on the tree.In the second, the coyote guides and prevents the squirrel from executing its evasive strategy. "

In short, if you want to defeat the squirrel, you have to squirrel out of the squirrel.

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