NEW YORKCharles Sawyers, MD, head of the new Human Oncology and Pathogenesis Program at Memorial Sloan-Kettering Cancer Center, is perhaps best known for his kinase inhibitor research leading to the development of imatinib (Gleevec) and dasatinib (Sprycel), drugs of unprecedented benefit for patients with chronic myelogenous leukemia.
Yet he began his career investigating hormone-refractory prostate cancer (HRPC), and prior to joining MSKCC was director of the Prostate Cancer Program Area at UCLA's Jonsson Comprehensive Cancer Center. Now, in a preclinical animal model of androgen-resistant HRPC, he has employed molecular approaches similar to those he used to study acquired resistance to targeted therapy of CMLand has made a profound discovery with the potential to change antiandrogen treatment of prostate cancer.
At the Chemotherapy Foundation Symposium XXV, in a special session entitled "The 21st Century Cancer Revolution," Dr. Sawyers shared provocative findings from a mouse xenograft study of RD162, the parent compound of MDV3100 (Medivation, Inc., San Francisco), a novel small molecule targeting the androgen receptor (AR) that is now under investigation in a multicenter phase I-II clinical trial.
The new agent is truly a next-generation antiandrogen, he told ONI: It only functions as an AR antagonist, in contrast to the antagonist-agonist conversion known to develop in men treated with bicalutamide (Casodex), the standard antiandrogen drug. And it shuts down AR activity not via increased AR binding affinity, but by actually changing AR conformation so it cannot bind to DNA.
Current understanding of HRPC, based on work in animal models, Dr. Sawyers said, is that it is still AR dependent: Knockdown of the AR impairs tumor growth, and HRPC progression occurs with AR overexpression.
Recent investigations by his group and others into the molecular basis for restored function of the AR in HRPC xenograft models suggests it results mainly from increased AR messenger RNA and protein levels (80% of cases), via receptor amplification or other mechanisms, and from AR gene mutation (10% of cases).
The findings, he added, are consistent with data from human samples showing higher AR levels in men with hormone-refractory vs hormone-sensitive cancer.