It's remarkably potent against two cancers so far, but will the same targeted strategy work with other malignancies? Researchers are hopeful but are keeping their expectations in check.

With Gleevec's dramatic success in muzzling the tyrosine kinases underlying chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GISTs), the search is on for compounds that inhibit other cancer-causing tyrosine kinases. One such drug, Herceptin, for patients with metastatic breast cancer and excess levels of the growth factor receptor Her2, was approved in 1998. Other inhibitors are in patient studies, including several that target tyrosine kinases serving as receptors for epidermal growth factor or vascular endothelial growth factor (VEGF). The VEGF receptor is of particular interest because it promotes growth of new blood vessels that feed tumors.

None of these inhibitors, however, are likely to match Gleevec's knockout performance against CML and GISTs, predicts Brian J. Druker, at Oregon Health Sciences University in Portland. Although they could be at least as effective as other cancer chemotherapies directed toward general growth processes, most will not squelch the cancer at its molecular source, Druker says. Even if they inhibit tyrosine kinases that are expressed in many cancers, expression is not enough. For inhibitors to strike with power and precision, their targeted molecules must be part of the cancer's root cause.

Indeed, Gleevec itself—now being tested in lung cancer patients—is unlikely to match its earlier successes. That's because although the drug's specific targets, ABL and c-KIT tyrosine kinases, may participate in the growth pathways of other cancers, they are less likely to be the root cause in those diseases, Druker explains.

Owen N. Witte, an HHMI investigator at the University of California, Los Angeles, is enthusiastic about testing Gleevec in other cancers, but he thinks the drug will prove most useful as part of combination chemotherapy. "When you have a drug that has limited side effects and can have efficacy in different settings, it should be tried," Witte says. "You may need to combine it with other drugs, but that's the history of chemotherapy for cancer—combinations of drugs work better for certain tumors." Likewise, inhibitors of the majority of other tyrosine kinases are expected to be most helpful as part of a multipronged treatment approach, stemming a cancer's growth while leaving its roots intact. —JW

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Reprinted from the HHMI Bulletin,
September 2001, pages 10-15.
©2001 Howard Hughes Medical Institute