Gleevec is a kinase inhibitor that has halted previously hard-to-treat cancers.
Making "smart" drugs
"It took 20 years from the time mutant kinases were discovered to the approval of Gleevec," says Dana-Farber's Thomas Roberts, PhD, who helped lay the groundwork for thwarting kinases, particularly in blood cancers. He did so with DFCI colleagues Charles Stiles, PhD, James Griffin, MD, and Brian Druker, MD, who's now at the Oregon Health Sciences Center. "If we find an entirely novel mutant kinase today," Roberts adds, "it would take two years or less" to begin clinical trials of an inhibitor (drug) to block it.
Gleevec, formerly known as STI-571, had been developed by Ciba-Geigy Corp. in Switzerland as one of many kinase inhibitors. The company, now called Novartis after a merger, was persuaded to try it against the uncommon and hard-to-treat cancer CML, caused by a chromosome abnormality that triggers a runaway kinase signal.
Initially approved only for CML, Gleevec rapidly gained federal approval for use against GIST in early 2002, thanks in part to research and advocacy by Dana-Farber's George Demetri, MD. It is now viewed as the wave of the future in cancer drugs.
Unlike standard chemotherapy drugs, kinase inhibitors are so specific that they spare normal cells and tissues. As a result, their side effects are much milder, and they can be taken orally rather than needing to be injected into veins.
Dana-Farber's Todd Golub, MD, divides his time between DFCI and the Whitehead Institute/MIT Center for Genome Research, a hub for decoding DNA information.
In a more recent discovery, Dana-Farber investigator Scott Armstrong, MD, and colleagues found a mutant kinase called FLT-3 in cells of a particularly aggressive type of infant leukemia. With this distinctive abnormal kinase, the disease warranted a new, specific name: mixed lineage leukemia. As with the case of CML and Gleevec, inhibitors already existed — four of them, in fact — for this kinase. Today, one inhibitor-based treatment is already in clinical trials, showing activity against a type of adult leukemia known as acute myelogenous leukemia. It is about to be tried in infants.
"We think that many, probably most, cancers involve mutant kinases," says Roberts. "I can't promise you that every kinase has an inhibitor, but I think it's going to be much closer to the rule than the exception."
The kinase hunt can be traced to a conversation between Sellers and Meyerson while flying to Montreux, Switzerland, in 2001 for a Novartis conference. "We were talking about the fact that if you really want to understand cancer, you need to understand the complete pattern of genetic changes in cancer cells that accounts for their malevolent behavior," recalls Meyerson, a molecular and cellular oncology researcher whose chief interest is lung cancer.
"Bill said, 'Let's start with the [mutant] kinases, because there are already drugs that can inhibit them,'" Meyerson says. He agreed. "The biggest impact we could have on cancer would be to find mutations that could immediately be translated into therapies."
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