With the massive influx of information on tumor genetic profiles, cancer researchers are designing better, targeted treatments for cancer, says Charles Sawyers. The HHMI investigator at Memorial Sloan-Kettering Cancer Center shared a 2009 Lasker award with HHMI investigator Brian Druker and with Nicholas Lydon formerly of Novartis. Their translational research led to Gleevec, a drug that has turned chronic myeloid leukemia (CML) from a fatal cancer into a manageable condition for most patients.
HHMI: WHAT IS TRANSLATIONAL RESEARCH?
CLS: Translational research is moving science from the lab into patients, and using modern scientific tools, like genomics, to conduct elegant experiments. This gets into personalized medicine: why does the drug work in you and not me? In many cases the answer can be discerned by studying the genome of the patient or of the tumor. In the last several years, the tools to unravel these mysteries have become ready for deployment in clinical situations.
HHMI: WHAT ARE SOME EXAMPLES OF TARGETED DRUGS THAT ARE IN CLINICAL TRIALS OR ARE BEING USED WITH PATIENTS?
CLS: Gleevec is clearly one. Herceptin for breast cancer is another famous one. There's a set of drugs that inhibit angiogenesis, the growth of blood vessels around the tumor. All of these are approved, widely used drugs. Many are kinase inhibitors. Kinases are enzymes that are frequently drivers of different cancers. So you match the right inhibitor to the right kinase, based on a genetic profile of the tumor.
But resistance is a problem, just as with chemotherapy. In the cases in which we've unraveled the cause of resistance, it's generally been mutation of the kinase that you were targeting initially. The strategy is to come up with kinase inhibitors that can shut off avenues of escape by blocking drug-resistant mutants of the original target. We can anticipate and come up with a rational strategy to develop a combination of drugs, much like the success with HIV. A cocktail of two or three drugs goes a long way at controlling disease.
HHMI: YOU'RE REALLY TAKING ADVANTAGE OF EVOLUTIONARY PRINCIPLES, AREN'T YOU?
CLS: Yes, it's Darwinian selection. You can think of the tumor as a little Darwinian experiment of survival of the fittest in the face of the drug. What's so exciting about translational research is we can see the relevance of the experiments so soon and test the predictions from the lab in patients early in the clinical development of a drug.
HHMI: WHAT MAKES CANCER SUCH A GOOD CANDIDATE FOR THIS APPROACH?
CLS: Two factors. One is that our understanding of the molecular causes of cancer has reached a crescendo. The National Cancer Institute's Cancer Genome Atlas has the audacious goal of defining every genetic alteration in every single kind of cancer, creating the official unabridged Webster's Dictionary of cancer mutations. Second, the advances in drug development. What was heresy 15 years ago is accepted today: if a group of biologists and clinicians agree that protein X is a cancer target, the baton can be handed to a chemistry team and they will come up with an inhibitor.
Photo: Elizabeth Weinberg
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