Invasion and Metastasis in Prostate Cancer

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DESCRIPTION (provided by applicant): Death from prostate cancer is associated with metastatic disease. Hepsin promotes prostate cancer progression and metastasis. This study will identify hepsin inhibitors and analyze their efficacy in inhibition of prostate cancer progression. This work should result in development of novel drugs that can be used in the watchful waiting cohort of prostate cancer patients to prevent cancer progression and development of deadly metastatic disease. PUBLIC HEALTH RELEVANCE: Hepsin is one of the most upregulated genes in human prostate cancer. It is overexpressed in up to 90% of primary prostate tumors with levels often increased >10 fold. Hepsin encodes a cell-surface serine protease that can activate the uPA proteolytic system and the HGF-MET cell scattering and invasion pathway. Overexpression of hepsin plays causal role in prostate cancer and promotes prostate cancer progression and metastasis. We hypothesize that pharmaceutical inhibition of hepsin's proteolytic activity will result in attenuation of prostate cancer progression and metastasis. In this case, small molecule hepsin inhibitors could prove to be very useful for treating the `watchful waiting' cohort of prostate cancer patients, to attenuate or inhibit primary cancer progression and, potentially, eliminate the need for surgical or radiological intervention in these patients. The major objective of this study is to develop small molecule hepsin inhibitors, analyze their pharmacokinetic properties and determine their efficacy in attenuation of prostate cancer progression in mouse models of metastatic prostate cancer. This study is developing a novel treatment approach and a novel therapeutic target for attenuation or prevention of metastatic prostate cancer.