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Novel_Target.com

Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA

Correspondence: Tito Fojo, M.D., Ph.D., Center for Cancer Research, Building 10, Rm 12N226, 9000 Rockville Pike, Bethesda, Maryland 20892, USA. Telephone: 301-496-2631; Fax: 301-402-1608; e-mail: tfojo@helix.nih.gov

Those who do not learn from history are doomed to repeat its mistakes...

For oncologists the message of the recent American Association for Cancer Research and American Society of Clinical Oncology (ASCO) meetings was clear: hope and optimism, sprinkled with bravado. In countless forums, we heard about a new era and predictions of the demise of cancer. A similar enthusiasm and aura of invincibility prevailed in some parts of the financial world not too long ago. But as the list of dot com casualties mounts, we would do well to consider the striking parallels and heed their lessons.

The catalyst behind oncologists' enthusiasm has been the cloning of the human genome, and the feeling that, having accomplished this task, no goal is insurmountable. Our financial colleagues felt much the same a few years back as faster, more sophisticated computers and an internet revolution took us where no one had been before.

In business, not a day went by without a crop of "novel" dot coms. Similarly with "novel targets," the pace has accelerated so that today nearly every issue of a cancer journal reports one or even several "novel targets."

Dot coms were the "new economy;" existing businesses, the "old economy." "Clicks" would replace "bricks and mortar." As dot coms proliferated, investors and young talent flocked to the unproven new ventures, while traditional businesses stalled. Anyone with investments in the "old economy" was considered dated and of questionable intellect. Yet, in the long run, old economy businesses continued to be profitable; while the overwhelming majority of dot coms hemorrhaged cash, and with rare exceptions failed to achieve profitability. In oncology we have "novel targets" and "established targets." The latter are also euphemistically called "validated targets." Financial investors, young scientists, and those seeking grant funding are flocking to "novel targets," ignoring "validated targets." And the intellect of any scientist interested in a traditional target is questioned. But years into our novel target revolution, it is still drugs aimed at established targets that cure or benefit the majority of our patients today.

Dot coms were viewed as immune from all the "business variables" that had encumbered traditional businesses. All that was needed were a few computers and a cohort of tech-savvy employees. Their need for traditional support was underestimated. In a similar way, proponents of novel targets view their molecules as "magic bullets," unencumbered by traditional obstacles. Novel drugs, we are led to believe, will be easy to formulate, easy to administer, have no problems with protein binding, nor be subject to metabolism, and will be immune from mechanisms of drug resistance. And, of course, they will be free of those pesky side effects.

As stock prices rocketed, the rules changed. P/E ratios (price/earnings ratios) long used among brokers as a reliable guide of a stock's value were replaced by "novel concepts." Earnings were no longer important, but instead a company's future sales were deemed more reliable. Analyst after analyst told us that a stock's value should be based on a company's promise, and not its current status. In oncology the rules have also changed to accommodate drugs aimed at "novel targets," and we are being told to change our expectations. Whereas we previously deemed a drug a failure if the product of a tumor's measurement in two dimensions increased by 25%, the new response evaluation criteria in solid tumors (RECIST) allow this product to increase by 44% before we call a new drug a failure. Furthermore, we are told not to be deterred by a lack of activity in clinical trials, so long as the drug is tolerable. Success can now be measured as stable disease, even with a duration of only a few months in phase I and II clinical trials. And we are told we don't need to cure cancer; we only need to make it a chronic disease—like diabetes. Which begs the question: what is wrong with those diabetologists trying to transplant islet tissue—don't they know anything about the virtues of a chronic disease?

As the dot com cemetery fills, we should pause and ask ourselves what lessons can we learn from the mistakes made by so many in the business community. Dot coms failed because they ignored the obvious: the ability to start a "novel" dot com does not "validate" its need. Indeed we did not need most dot coms. Dot coms failed because they believed they would be supported by computers without much need for traditional infrastructure. But as they quickly learned, they needed warehouses and distribution centers, a platoon of "non-techies" to handle orders and returns, and a means to ship their products. Dot coms failed because they did not plan for adversity, nor for the obstacles they would encounter. They failed because they cast aside traditional ways of assessing "value" and set new, artificial standards. They failed because they made erroneous assumptions: demonstrating that Amazon could sell books was not evidence it could sell refrigerators. And as a "community," the financial markets failed because in the end, even the skeptical (Alan Greenspan) muted their opposition and let advocates with self-interests carry the day. In failing, they put our economy and the investments of many in jeopardy, while jeopardizing traditional businesses by not supporting them.

Because as oncologists we must protect our patients, not intangible "paper wealth," we must do everything to avoid failing. We must recognize that simple identification of a target does not mean it is indispensable for a cell. Indeed, the overwhelming majority of "novel targets" are likely to be of no therapeutic value. We must prepare for adversity. A drug designed for a novel target is just a molecule like so many others before, likely to be subject to the same adversity all previous molecules have encountered: pharmacokinetic interactions, resistance mechanisms, and pesky side effects. Already, we have reports of STI571 (Gleevec) resistance mediated by amplification of the bcr-abl fusion gene and acquired mutations. Stay tuned. And we must recognize a drug's limitations: while Gleevec effectively targets bcr-abl, it may perform less well against other kinases (c-kit). We must also not lower our standards. Lower standards do not lead to success, they only delay failure. Are we sure our traditional measurements were wanting? Are we sure our principal goal should be anything other than curing cancer? Finally, as a community we must remain skeptical, and question our new priorities. We must demand proof and results. Until proven effective, a novel target is simply a "target wannabe."

But there is hope. Business has realized that clicks need not replace bricks and mortars, but that "clicks and bricks" can be a winning combination. We too must realize that drugs targeting novel and "validated" targets must be developed and used together where possible. Indeed, numerous abstracts combining new and old were presented at the recent ASCO meeting. Such an approach may provide us with winning combinations, provided the new agent has activity, and is not "just along for the ride with a validated agent."

We would do well to learn from the lessons of others now. If we don't, we'll end up with a cemetery full of "novel agents." What will be the names on the tombstones? MMPI.com? FTI.com? NovelAntiAngiogenesisAgent.com? Or maybe, GenericCyclinInhibitor.com?

Tito Fojo, M.D., Ph.D. Center for Cancer Research, National Cancer Institute Bethesda, Maryland, USA

Received June 14, 2001; accepted for publication June 18, 2001.

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