Rapid Advances in Overcoming Drug Resistance to Molecularly Targeted Therapies
Virtually every oncologist has been faced with a patient who developed resistance to a chemotherapy treatment that had been working - this is called acquired drug resistance. Targeted therapies are not immune to this phenomenon, including the most successful targeted agent, imatinib (Gleevec).
The FDA's approval of imatinib for the treatment of chronic myeloid leukemia (CML) in 2001 launched the era of targeted therapy for cancer treatment. The drug directly inhibits an abnormal protein tyrosine kinase on white blood cells called BCR-ABL that, instead of regulating cell growth, remains continually active, fueling uncontrolled cancer cell growth in this form of leukemia.
"Many patients who initially respond well to imatinib therapy are at risk of developing resistance to the drug and suffering relapse - even those whose disease may appear to be in complete remission," explains Dr. R. Allan Mufson, chief of the Cancer Immunology and Hematology Branch in NCI's Division of Cancer Biology. Resistance comes on, Dr. Mufson adds, as the leukemia cells begin to derive mutations in BCR-ABL that prevent the drug from binding, rendering it impotent.
"We now know of over 30 different mutations that can cause BCR-ABL to become resistant to imatinib," says Dr. Charles Sawyers of UCLA's Jonsson Cancer Center. "In patients with newly diagnosed disease, we are seeing resistance to imatinib in about 4 percent of patients per year. The further the disease has progressed before initiating imatinib treatment, the greater the chances are that resistance will arise."
In many cases, practicing oncologists whose patients become resistant to chemotherapy have few, if any, options to combat the problem. But that's beginning to change. Recent advances in understanding the molecular basis of many cancers are allowing researchers to reverse engineer therapeutics by identifying the source of resistance and developing agents to combat it. The rapid development and testing of several second-generation therapies aimed at overcoming imatinib resistance is a case in point.
Studies on two new compounds - BMS354825 and AMN107 - have generated excitement. Like imatinib, both agents inhibit the aberrant function of the BCR-ABL kinase. Bristol-Myers Squibb (BMS) was already developing BMS354825 to inhibit a closely related kinase in solid tumors. Following Dr. Sawyers' presentation at a scientific conference on potential methods to combat imatinib resistance, BMS officials contacted him to see if their agent might fit the bill. AMN107, on the other hand, was specifically designed by Novartis to overcome imatinib resistance based on their studies of the molecular interactions between BCR-ABL and imatinib. Both new drugs are less specific than imatinib, which allows them to bind and inhibit many imatinib-resistant mutants. They are also more potent than imatinib, meaning less of the drug is needed to cause the same biological effect.
"Preclinical studies show BMS354825 is about 300 times more potent than imatinib, and AMN107 is about 20 times more potent than imatinib," says Dr. Sawyers.
Last summer, Dr. Sawyers and colleagues published a report in Science on their preclinical studies with BMS354825. The drug, they reported, was effective against 14 of the 15 different imatinib-resistant mutations tested, and significantly prolonged the survival of mice with CML.
Based on these studies, BMS began a phase I clinical trial in conjunction with Dr. Sawyers and Dr. Moshe Talpaz at M.D. Anderson Cancer Center. Preliminary trial results, reported in December 2004 at the American Society of Hematology Annual Meeting, showed that BMS354825 overcame imatinib resistance in 31 of 36 patients.
"We have seen outstanding responses with no side effects in patients with all phases of the disease," comments Dr. Hagop Kantarjian, another clinician involved in the clinical trial and principal investigator of the leukemia-focused NCI Specialized Program of Research Excellence at M.D. Anderson.
While the phase I trial with BMS354825 is almost complete, Dr. Sawyers explains, "Our results to date are so promising that we have already begun the phase II portion."
Preliminary results from the phase I trial testing AMN107 in patients with imatinib-resistant disease show no adverse effects in any of the 95 patients treated, says Dr. Kantarjian, who also is involved in trials developing that agent. "Most of our patients are in later stages of the disease, and we are getting an early response rate of about 50-60 percent." Currently researchers are correlating responses with particular BCR-ABL mutations and trying to determine the optimal dose for the phase II portion of the study.
"Both BMS354825 and AMN 107 seem to have similar clinical potency. These new drugs pave the way for designer cancer treatments that could be used as second-line therapies for those who develop resistance to imatinib," says Dr. Kantarjian. "Alternatively, these drugs could be administered as an initial kinase inhibitor cocktail to prevent the development of resistance to any of the particular drugs - akin to how protease inhibitor cocktails are used to treat HIV."
By Sunil Jani