The progression of prostate cancer to an androgen-refractory state is characterized by pronounced heterogeneity in the genetic and cellular defects that support survival and proliferation in the face of potential therapies, such as androgen withdrawal or cytotoxic chemotherapy. Among these multiple defects is the dysregulation of androgen receptor (AR) function. Indeed, evidence implicates functional AR as a key factor in the recurrent growth of human prostate tumors after androgen depletion, and defines a need for therapeutic strategies that include the targeting of AR to improve the treatment of androgen-independent prostate cancer and, ultimately, to increase the survival of HRPC patients.
Our laboratory has recently developed a distinct class of novel agents that is capable of inhibiting the production of AR by prostate cancer cells leading to cancer cell death. We believe that the lead compound, OSU-CG12, can be further modified to generate agents of even greater potency. Thus, the objectives of this research project include the synthesis of a library of new OSU-CG12 derivatives, the identification of the most potent of these compounds with respect to AR suppression and anticancer activity in vitro, and evaluation of the tumor suppressive efficacy and toxicity of these compounds in a well-established mouse model of androgen-independent prostate tumor growth.
In accordance with our long-term goal of developing novel effective chemotherapeutic agents, we expect the results of these proposed studies to provide a strong rationale for the translation of these agents to clinical trials of prostate cancer therapy. Should these agents move forward clinically, men who experience tumor recurrence after androgen withdrawal would likely be the primary beneficiaries of these agents.