Evaluation of the Role of PSA Inhibitors in the Prevention and/or Therapy of

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Prostate cancer cells, like normal prostate secretory-luminal epithelial cells, produce very high levels of the PSA. PSA is aptly named, in that it is produced at high levels exclusively by prostate cells and is not produced in significant amounts by any other normal tissue in the human male. PSA is a chymotrypsin-like serjne protease that is used extensively as a biomarker to screen for prostate cancer, to detect recurrence following local therapies and to follow response to systemic therapies for metastatic disease. PSA, however, is also a well credentialed therapeutic target for prostate cancer. The focus on PSA's role as a biomarker has made perhaps made "PSA" synonymous with "biomarker" and this may explain why PSA has not been given consideration as a therapeutic target. However, a significant number of studies have also implicated a role for PSA in the pathobiology of prostate cancer. These studies emphasize the importance.of PSA as a therapeutic target for prostate cancer. Therefore, the hypothesis of this project is that small molecule inhibitors of PSA's enzymatic activity will have therapeutic efficacy against prostate cancer local growth, progression and/or metastases. The goal of this project, therefore is to identify and develop novel small molecule inhibitors of PSA. To achieve this goal, we propose the following Specific Aims. In Specific Aim 1, we will synthesize and evaluate a series of peptide based PSA inhibitors for their ability to specifically inhibit PSA vs. other extracellular proteases. In Specific Aim 2, we will evaluate candidate inhibitors in vivo to determine pharmacokinetics, toxicity and efficacy against isogenic PSA positive and negative human prostate cancer lines. In Specific Aim 3, we will perform correlative studies to assess biodistribution of these PSA inhibitors and to determine effect of PSA inhibition on serum PSA levels. As a component of this aim, we will also evaluate the potential of radiolabeled analogs of these PSA inhibitors as imaging agents for prostate cancer. Finally, we will develop a serum based test to quantify PSA inhibition that can be used to optimize dosing regimens and that ultimately could be used to validate adequate target inhibition in clinical studies without requiring tissue biopsy. The relevance of this research to public health is that PSA inhibitors have potential in both the treatment and detection of prostate cancer. In this proposal we will perform the required preclinical laboratory studies needed to determine if clinical testing is justified.