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With cancer drug resistance, play chess, not tennis

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By Anette Breindl, Science Editor

When cancers become resistant to the drugs used to treat them, it has become possible – at least in principle – to understand the cause of that resistance through sequencing, and if a drug exists that is effective against cells with the mutation, to change a patient's treatment accordingly. But a better strategy might be to prevent resistance from developing at all.

At the recent annual meeting of the American Association for Cancer Research, Robert Beckman, a former Merck & Co. Inc. executive who is the founder of Onco-Mind LLC, argued that cancer treatment needs to become more strategic.

"In chess, we have very complex strategies designed to win," he told the audience. "With cancer patients our strategies aren't as complex."

Not that Beckman doesn't understand why. In cancer chess, "there are so many thousand pieces that we are lucky if we can just identify them all."

But the unfortunate consequence is that current treatment strategies bear more resemblance to tennis than chess – serve as hard as you can, and then focus on the ball that is coming over the net right now, rather than taking a moment to consider the future.

Beckman argues that such a strategy is short-sighted. It can be more important, he said, to "focus on the prevention of resistance as opposed to treating the tumor you see."

MATHEMATICAL MODEL

During a stint at Princeton University's Institute for Advanced Studies Beckman and his colleagues published a mathematical modeling study of 3 million virtual patients, testing whether there were drug regimens that could improve the long-term success at keeping tumors at bay than current standards of care. They found such regimens for a third of their virtual cases.

"If you understand the underlying evolutionary dynamics and think ahead, you get different recommendations" for treatment, he told BioWorld Insight. "And counterintuitive recommendations may be beneficial." In one striking case, the treatment suggested by the model as the best way to prevent resistance in the long term would have allowed slow growth of the tumor in the short term.

Convincing an Institutional Review Board, the FDA, or the patients themselves that the best thing for a patient is to let their tumor grow slowly for now while you take care of resistance that has not yet arisen will take more than modeling data. "A large body of data would have to be accumulated before you could do a clinical trial on this," he said.

Beckman is now working on testing some of the suggestions made by the mathematical algorithms in cell cultures and animal models. Ultimately, the first such clinical trial would probably be on already FDA-approved agents combined or sequenced in different ways.

Such sequencing is one example of a more general principle, namely, that the dosing schedule of drugs has an impact on how well they work.

Larry Norton at Memorial Sloan-Kettering Cancer Center in New York has done a great deal of work on such scheduling. He was a pioneer of the idea that dose-dense scheduling, that is, administering the chemotherapy more frequently at lower doses rather that less frequently at higher doses, improved survival.

Norton said that ultimately, personalized dosing schedules will become a part of personalized medicine just as much as targeted therapies.

"We knew empirically in the '70s that schedule was important," he told BioWorld Insight. By looking at the effects of chemotherapy in day-to-day detail, Norton and colleagues showed that when a drug is given over a two-week period, "efficacy occurs by day eight or 10 . . . Most of the second week was not effective, and was causing nothing but toxicity."

In fact, he said, "The single worst thing you can do is constant exposure."

Much of Norton's work has been done on chemotherapies, but his team has shown that the same principles hold for the targeted agents. Everolimus "should not be given continuously, lapatinib should not be given continuously."

The reason is that "every agent that is not 100 percent effective induces its own mechanism of resistance," he said. "The cells that are not killed are able to defend themselves by upregulating other mechanisms."

IT TAKES TIME

"But," he added, "that takes time."

And so, by giving cells breaks from drugs at the right time, there is no incentive or time for cells to develop such resistance mechanisms, which often make them grow more slowly.

Norton said that repeated cycles of treatment can take care of those tumor cells that were not killed the first time around. "If you do it right, my expectation is that ultimately you can kill them all."

"Physics tells us the same thing," he said. "Imagine being in a pool, up to your chest in water, and walking across. If you take one step and pause, and another step and pause, it's pretty easy to get across the pool. Whereas if you try to go as fast as possible, you will induce resistance and it will become much harder."

While preventing resistance is the best option, it may not always be a realistic one.

Using drug combinations up front is a big part of what has turned HIV from death sentence into chronic illness. But cancer is more complex than HIV.

Gideon Bollag is the CEO of Plexxikon Inc., the developer of BRAF inhibitor Zelboraf (vemurafenib). Zelboraf is a targeted therapy that prolongs survival in melanoma, for a time. But ultimately, patients become resistant to the drug in a multitude of ways. There are "at least half a dozen prominent resistance mechanisms," Bollag told BioWorld Insight, along with additional minor players. "And so it's hard to standardize" treatments in a way that prevents resistance.

"Will there be a single agent that will combine with a BRAF inhibitor to prevent resistance?" he asked. "It's unlikely."

But there might ultimately be several such strategies. Clinical trials combining BRAF with MEK inhibition have shown some promise – somewhat surprisingly, since MEK is in the same pathway as BRAF and "it wasn't predicted in the beginning that targeting the same pathway twice would give you a lot of synergy."

Another possibility is to combine BRAF inhibition – or, probably, other targeted therapies – with immunotherapy. Though the initial attempts to combine Zelboraf with cancer immunotherapy Yervoy proved too toxic, Bollag said, "everyone is hopeful" that it will be possible to develop such a combination.

Immunotherapy in general has high hopes riding on it for being relatively resistant to resistance – because, like tumors themselves, the immune system's response to them can evolve over time.

Speaking at last year's American Society of Clinical Oncology meeting, Suzanne Topalian, principal investigator on studies of Bristol-Myers Squibb Co.'s immunotherapy nivolumab told the audience that resistance to immunotherapies can also occur, and is more likely the more targeted those therapies are.

But Topalian's prediction was that broad targeting of immunotherapies could ultimately forestall resistance by cutting off cancer's escape routes.

A "properly educated immune system," she said, "will be able to keep up with tumors."