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By Malorye A. Branca

February 18, 2004 | Thwarted in their goal of finding “smart drugs” that obliterate tumors with a single shot, oncologists are turning instead to compounds that hit multiple targets simultaneously. “I call it pharmaceutical sniping,” said Pfizer’s Judith Sebolt-Leopold at a recent American Association for Cancer Research (AACR) meeting in Boston.

The concept of disarming cancer cells by hitting them squarely at their weakest spot has long been an ideal among drug makers. Nature, of course, is much more complicated. “Once you take drugs through clinical trials,” says Spiro Rombotis, CEO of Cyclacel, “you start to see that even the same kinds of tumors can have different targets.” Worse still, those targets change as the tumor spreads -- as experience with Novartis’ Gleevec demonstrates only too well.

Developers are also realizing that even the most precisely targeted drugs can have negative “off-target” effects. But according to Sebolt-Leopold, “additional activities can be a plus if toxicity is acceptable.” A drug that hits cancer cells at multiple points could make for a better treatment overall.

Pfizer is pursuing this tack with SU11248, a drug that targets FLT3, an exciting new cancer target, but also knocks down other important proteins, including PDGF, VEGF, and KIT. Pfizer acquired the drug, hailed by some as “the next Gleevec,” along with Pharmacia last year. In a similar vein, Pfizer is developing compounds that attack MEK, a key signaling protein.

One of Pfizer’s MEK inhibitors is so potent it can be given only in minute doses, which made it challenging to formulate an actual drug from it. The company was able to do so, however, and the drug is going into trials. Structural analysis of the MEK protein was “critical” in explaining why this drug binds so tightly to MEK and not other molecules.

Cyclacel’s approach involves an arsenal of drugs aimed at multiple targets in different stages of the cell cycle, aimed at curtailing cancer cells from growing and dividing.

Cyclacel’s lead compound is CYC202, a cyclin-dependent kinase inhibitor. At the AACR meeting, the company announced it has discovered a series of drug candidates that inhibit another molecule involved in cell growth -- Polo-like kinase 1 (PLK1). These targets, Rombotis says, can be disrupted more easily in malignant cells than their normal counterparts because cancer cells are already unstable. “We are still at the early stages of mapping out which functions correspond to selectivity,” he says.

William Slichenmyer, Pfizer’s vice president of oncology development, says there is “growing theoretical support” for treating cancer with cocktails of targeted therapies -- “multiple drugs, each given at the right dose, and at the right time” (see “Targeting Tumors,” Aug. 2003 Bio-IT World, page 40). That means understanding their activity, and knowing who should receive them. “As a practicing physician, you really get your nose rubbed into it,” says oncologist Cy Stein. “If you get too specific with therapy, the cancer laughs at you and finds a way to get around it.” 


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