The goal of this project is to develop compounds with characteristics that are likely to provide effective antitumor activity against androgen dependent prostatic cancer. Our strategy is to identify compounds which achieve total androgen blockade. During the current grant period, we have discovered a number of potent inhibitors of 17alpha-hydroxylase/C17,20-lyase. Several of these also inhibit 5alpha-reductase and/or are antiandrogens. We plan to continue studies of these compounds utilizing the methods we have established to characterize their activity. Because mutations of the androgen receptor appear to play an important role in resistance to current therapy, we will modify inhibitors in order to increase their activity as androgen receptor antagonists for both the wild type receptor and the mutated forms common in prostate cancer. We propose methods to improve the bioavailability of our most potent inhibitors including synthesis of analogs of our inhibitors to increase efficacy in vivo. We will also synthesize radiolabeled inhibitors to determine their pharmacokinetics and metabolism. The specificity of inhibitors will be determined by investigating their effects on other steroidogenic enzymes. We will determine whether the inhibitors are androgen receptor agonists or antagonists by their effects on transcriptional activation assays, prostate cancer cells in culture, and in histocultures of samples from patients. We will study their effects in vivo on androgen concentrations and prostate weight in normal male rats. The antitumor efficacy of the most potent inhibitors at optimal dose/route will be investigated in mouse xenograft models with human prostate cancers (PC-82 and LNCaP) including the effects of inhibitors on tumor proliferation/apoptosis. These studies should enable us to select the most effective inhibitors by the end of the grant period, that can then be advanced to phase I trials.
