A strong foundation
Brian Druker, MD, spent a decade training and researching at DFCI, where he was
instrumental in developing Gleevec.Druker says his Dana-Farber training was vital in preparing him to take the Gleevec effort to its next — and successful — level. "There's no question the scientific environment at Dana-Farber is second to none," he said recently. "Getting the training in Tom Roberts' lab and being able to work with someone like Jim Griffin was critical in my own development."
In 1993, Druker joined Oregon Health Sciences University, where he continued to pursue the CML project. He asked Ciba-Geigy's scientists for some drug compounds that might block the tyrosine kinase-signaling pathway in CML cells. Ultimately, he identified a compound called STI-571 (later named Gleevec) that killed CML cells in the laboratory. It turned out that STI-571 interrupts at least two other signaling pathways in addition to BCR-ABL: one is called PDGF and the other, c-kit — the overactive pathway in the GIST tumors that Demetri would treat with Gleevec.
Despite the promise of STI-571 in the laboratory, Novartis (of which Ciba-Geigy was now a part) wasn't eager to produce enough for clinical trials unless there was evidence it might work in cancers besides CML. So a Novartis scientist asked Stiles to test STI-571 in rats with glioblastoma, a brain cancer. The drug showed activity against the cancer, and Novartis decided to produce Gleevec for clinical testing. (STI-571 is being investigated in human brain tumor patients, but no data have been released.)
By 1999, Gleevec was being tested in early phase CML patients with resounding results. Each of the first 31 patients to take effective doses of the drug had white blood cell counts return to normal. The drug proved less effective, but still remarkably helpful, in the late, life-threatening phase of CML.
Some Phase II CML trials with STI-571 were carried out under Stone's direction at Dana-Farber. With some 130 patients treated several clinical trials here, the record shows those in later stages of the disease — especially in what's known as "blast crisis" — don't respond as well as patients in earlier stages, and those who do respond may relapse. Advanced CML cancers often develop resistance to Gleevec, allowing the disease to survive despite the drug. Researchers hope that combining Gleevec with other drugs will overcome the cancer's resistance.
Meanwhile, Novartis has reported that data from Phase II trials of Gleevec indicate the medication is even more effective in all three phases of CML than it had first appeared.
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