Promoting the Development and Delivery of Targeted Therapies
Earlier this month at the American Association of Cancer Research annual meeting, impressive data were presented from a phase II trial testing the multitargeted kinase inhibitor dasatinib (BMS-354825) in patients with chronic myeloid leukemia (CML) who had failed to respond to or had developed resistance to imatinib (Gleevec). In chronic-phase CML patients, for instance, 93 percent had a complete hematologic response, meaning normal blood counts and no CML-related symptoms.
Imatinib has rightfully been heralded as a breakthrough drug. Dasatinib is an excellent example, though, of how cancer researchers are learning from the successes and failures of targeted therapies like imatinib to make important advances in the development of next-generation targeted agents. Not only does dasatinib have a 325-fold stronger affinity for its gene target, BCR-ABL, than imatinib, it also appears to be effective against 18 of the 19 identified mutated forms of BCR-ABL - the very mutations that drive imatinib resistance.
It is this latter observation concerning overcoming the problem of acquired resistance to molecularly targeted therapies that I find most intriguing. From our work on CML resistance to imatinib, and several other molecularly targeted therapies, it appears that the cancer cells become resistant to therapy by the development of further mutations in the targeted pathway and not by mutations or genetic alterations occurring as random events in any critical signaling pathway within the cancer cell. The importance of this, if it holds to be true, is a tremendous economy of scale allowing investigators to focus the study of developing resistance on the original pathway.
Even with the interest and optimism generated by these initial targeted therapies, we must acknowledge that this is a field very much in its infancy. NCI is engaged in efforts on many fronts, intramurally and extramurally, to accelerate the progress in this area. NCI intramural researchers, for example, are identifying important new molecular targets and utilizing high throughput screening of chemical and natural product libraries, developing drugs that inhibit them. Among these is 17-DMAG, a second-generation inhibitor of heat shock protein 90, that has the potential to treat many tumor types.
But NCI's involvement in targeted therapy research goes beyond the work of individual NCI labs or researchers. It is remarkably comprehensive and involves collaborations and partnerships in areas such as molecular imaging, toxicology, drug design, and early phase clinical trials supplemented by intense correlative studies.
One example is the Molecular Targets and Molecular Oncology Center of Excellence, a multifaceted effort that brings together intramural and extramural labs. Through this program we are working with private-sector companies to bring new molecularly targeted screening-platform technologies to NCI. As a result, we already have launched individual projects to screen millions of compounds to determine if they have activity against new molecular targets.
NCI's Cancer Therapy Evaluation Program (CTEP), meanwhile, has had great success working with industry to test combinations of targeted agents. While targeted agents are powerful in their own right, the research community and industry agrees that combining targeted agents will greatly increase their efficacy, and in fact may be essential. To date, CTEP has begun some 100 clinical trials featuring combinations of targeted agents, most of which have been started in the past 2 years.
Finally, through partnerships with extramural investigators, industry, and other private entities in the areas of screening, imaging, and preclinical pharmacology, we are moving to formalize a cancer therapeutics development consortium. Through this partnership we will conduct the so-called phase 0 studies to facilitate rapid screening of new targeted agents in humans before taking them into more full-scale development. The program also will launch a new national clinical target validation lab to find new ways to analyze the effects of small-molecule anticancer drugs.
NCI has made a major commitment to supporting the development of genomic and molecular assays to identify the patients most likely to benefit from a particular therapy regimen. As cancer researchers become more adept at developing molecular profiles of individual patients' tumors, we will ensure that many more patients receive a treatment with the best chances of success. This is the true promise of molecularly targeted therapies.
Dr. John E. Niederhuber