Invasion and Metastasis in Prostate Cancer

描述（由申请人提供）：前列腺癌死亡与转移性疾病相关。肝素促进前列腺癌的进展和转移。本研究将鉴定hepsin抑制剂并分析其抑制前列腺癌进展的功效。这项工作将导致新药的开发，这些新药可用于观察等待的前列腺癌患者队列，以防止癌症进展和致命转移性疾病的发展。公共卫生相关性：Hepsin是人类前列腺癌中表达上调最多的基因之一。它在高达90%的原发性前列腺肿瘤中过表达，其水平通常升高10倍。Hepsin编码一种细胞表面丝氨酸蛋白酶，可以激活uPA蛋白水解系统和HGF-MET细胞的散射和侵袭途径。hepsin过表达在前列腺癌中起因果作用，促进前列腺癌的进展和转移。我们假设药物抑制hepsin的蛋白水解活性将导致前列腺癌进展和转移的衰减。在这种情况下，小分子肝素抑制剂可能被证明对治疗“观察等待”的前列腺癌患者非常有用，可以减轻或抑制原发性癌症的进展，并有可能消除这些患者手术或放射干预的需要。本研究的主要目的是开发小分子hepsin抑制剂，分析其药代动力学特性，并确定其在转移性前列腺癌小鼠模型中抑制前列腺癌进展的功效。本研究正在开发一种新的治疗方法和新的治疗靶点来抑制或预防转移性前列腺癌。

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.