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Another shift in cancer research

by Robert Teitelman  |  Published June 6, 2011 at 3:51 PM
cells125x100.jpgRon Winslow in Monday's Wall Street Journal offers up a story on cancer research that is bedecked well above the fold by a headline that has been written many, many times before: "Major Shift in War on Cancer." Indeed, there have been major shifts in the war on cancer declared since the war began, back in the Nixon administration, often coinciding with big annual cancer research meetings that attract reporters, like the American Society of Clinical Oncology meeting in Chicago that Winslow attended. (This isn't Winslow's fault, but what kind of story are you going to pitch editors after a cancer meeting: no hope, no news?) Old-timers will recall the interferons, the interleukins, monoclonal antibodies, immune therapy, oncogenes, genomics, angiogenesis, stem cells. All of these were scientifically valid, some even clinically exciting, if prone to hype. But still the war drags on. Winslow's new paradigm is so-called personalized cancer therapies, which is less a single biological tactic than a broader strategy: to step back from an approach that goes after cancer as a single disease caused by a handful of cellular malfunctions, and begin to focus on it as a very individual malady. As Winslow says, this isn't new; what's new is some clinical evidence that the approach has quantifiable promise. The personalized approach emerges from a long debate within cancer research that often seemed to lay people and some researchers to be absurdly philosophical. Is cancer a homogenous disease that can eventually be "cured" by investigation of fundamental cellular malfunctions, or is it a heterogeneous jumble of tumors and mutations?  For decades, the big money went to research that aimed at the homogenous argument: Hypotheses like oncogenes or of "natural" products like the interferons or interleukins in the '80s were driven by the belief -- really the hope -- that there were switches common to all, or at least many, cancers. Even the genome projects of the late '90s were marketed to a broader public as a way to discover the genetic basis of cancer, dangling the hope of a broadly homogenous "cure." (These approaches always raised the most money, which certainly added to their allure.) But in fact, that approach has been battered, as every advance seemed to throw up greater complexities. As Winslow writes: "Many tumors are complex organisms fueled by multiple pathways. When one is disrupted even by a potent single agent, others compensate to help tumors develop resistance to treatment."
What we're seeing now is the gradual retreat of the cancer-as-homogenous-disease in the face of empirical realities. It is unlikely to ever disappear; an underlying mechanism, after all, remains the alchemist's stone of cancer research. Besides, personalization may well be important, though one would be wise to retain some skepticism. Winslow's conclusion, for instance, that immediately follows his description of biological complexity reflexively offers the newest hope: "Targeted therapies will likely be more effective when given in combination with similar agents or in some cases existing treatments." Will likely? Maybe. Maybe not. Knowledge of cancer research history habituates all but the most naive observer to an abiding skepticism.
Still, this personalization approach, if it continues, would change the economic fundamentals of drug development and commercialization. As Winslow says, offering up combination therapies could be extremely expensive, particularly if they are very narrowly defined -- as the "personalization" approach would seem to demand. Companies will have to engage in more collaboration (to share costs) and joint ventures (to share products). Enormous amounts of clinical research and testing will be required; some of that's already occurring. But combinations generate complexities rather than simplify them. What are optimal combinations, dosage levels, side effects? Can diagnostics to highlight these specific mutations or markers in individuals be effectively developed? And, again, who will pay for all this research into what may turn out to be a limited market for a certain kind of tumor mutation? And who will pay for what seems certain to be a pretty expensive therapy?  
The effect of all this on commercial drug development remains murky. To make personalized cancer therapy work would seem to demand continued high federal funding of academic research, particularly on the clinical side where much of this testing will take place. Personalized medicine, which is really a very hard slog through one kind of tumor after another, would seem to play more into the strengths of biotechnology companies than, say, Big Pharma. But that too may be a superficial reading. Big Pharma still has the money and, in many cases, the compounds or biologicals that make up combinations. Their big problem will be that given their enormous size, their shareholders are unlikely to tolerate extremely long-term projects aimed at a series of individual, niche markets.
Stepping back, Winslow's report on personalized cancer therapies does provide a splash of cold water for those who believe penetrating nature's secrets is as straightforward as, famously, sending a man to the moon. Cancer research has, since the war on cancer began, been something of a paradox: what seemed to be great advances into the inner workings of biology but turned out to have very spotty clinical results. The great promise of both the war on cancer and biotechnology that "cures" could be developed once a full understanding of biological pathways was gained has proved elusive. Progress has been slow. Personalized medicine borrows from that belief, but it represents a retreat from universal to local causes. We are edging from belief in overarching biological theory to an acceptance of empirical reality; in some ways it's a throwback to the days before molecular biology promised to transform the paradigm of drug discovery.
For now heterogeneity seems to be winning out over homogeneity. Not to make too much of this, but we are currently living in a turbulent age when universal solutions have proved to be less-than-advertised, particularly when it comes to individual lives amid local conditions. "Scientific Marxism" has died as a governing philosophy. The Arab Spring continues. And then there's the dismantling of theories based on homogeneity in neoclassical economics: from the self-evident failures of the rational expectations hypothesis to that of the New Keynesians. We are suckers for a good story, for relative simplicity and for hope. But the teeming world, social or natural, within and without, doesn't always cooperate. - Robert Teitelman
Tags: Big Pharma | biotechnology | cancer | heterogenous | homogenous | Ron Winslow | The Wall Street Journal
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