A New Mechanism for Castration Resistant Prostate Cancer

描述（由申请人提供）：来自基础、转化和临床研究的新证据表明，HGF/c-Met信号通路在前列腺癌进展和CRPC发展中的重要性。肝细胞生长因子（HGF）通过其受体c-Met在调节细胞生长、细胞运动、形态发生和血管生成中起着至关重要的作用。HGF和c-Met轴是上皮-间质相互作用的重要贡献者，直接促进前列腺癌的进展和转移。c-Met表达上调已在大多数转移性前列腺癌病变中观察到。有趣的是，尽管c-Met在前列腺癌中表达的发生率很高，但c-Met扩增仅在约10%的转移性前列腺癌中观察到，这表明c-Met异常表达的其他调节机制。在我的实验室所做的基准工作已经证明了AR作为前列腺癌细胞中c-Met表达的转录抑制因子的新作用。我们的发现不仅阐明了前列腺癌细胞中c-Met表达的异常调控，而且暗示了当前雄激素消融治疗诱导CRPC发展的新机制。目前的雄激素消融治疗在抑制AR诱导的促生长基因表达激活的同时，也减弱了AR对c-Met表达的抑制，导致肿瘤细胞中c-Met的增加。由于c-Met的过表达与更具侵袭性的前列腺肿瘤表型直接相关，在目前的雄激素消融单药治疗中加入c-Met抑制剂可能改善临床结果，延缓和预防CRPC的发展。因此，在这个修改后的R01申请中，我们提出了三个独特但综合的特定目标来直接验证我们的中心假设：通过当前雄激素消融治疗抑制雄激素作用增加c-Met表达，从而促进肿瘤侵袭、激素难治性和转移；联合抑制AR和c-Met致癌途径可以预防或延缓CRPC的发展。这项及时的研究旨在开辟新的领域，改变目前治疗晚期前列腺癌的模式。本研究产生的数据应为临床干预致死性CRPC提供关键和必要的科学证据，以提高数十万男性的生存率。

DESCRIPTION (provided by applicant): Emerging evidence from basic, translational and clinical studies has shown the significance of the HGF/c-Met signaling pathway in prostate cancer progression and CRPC development. The hepatocyte growth factor (HGF) plays a critical role through its receptor c-Met in the regulation of cell growth, cell motility, morphogenesis, and angiogenesis. The HGF and c-Met axis is a significant contributor to epithelial-stromal interactions, which directly contributes to prostate cancer progression and metastasis. Up-regulation of c-Met expression has been observed in most metastatic prostate cancer lesions. Interestingly, despite the high incidence of c-Met expression in prostate cancer, c-Met amplification was only observed in about 10% of metastatic prostate cancers, suggesting other regulatory mechanisms underlying aberrant expression of c-Met. The benchwork done in my lab has demonstrated a novel role of AR as a transcriptional repressor in c-Met expression in prostate cancer cells. Our finding not only elucidates an aberrant regulation of c-Met expression in prostate cancer cells, but also implicates a novel mechanism by which current androgen ablation therapy induces CRPC development. While current androgen ablation therapy suppresses activation of the growth promoting gene expression induced by the AR, it also attenuates AR repression of c-Met expression, resulting in an increase of c-Met in tumor cells. Since overexpression of c-Met directly correlates with more aggressive prostate tumor phenotypes, adding c-Met inhibitors to current androgen ablation monotherapy may improve clinical outcomes, and delay and prevent CRPC development. Thus, in this amended R01 application, we propose three unique but integrated specific aims to directly test our central hypothesis: Inhibition of androgen action through current androgen ablation therapy increases c-Met expression thereby promoting tumor invasion, hormone refractoriness, and metastasis, and combined inhibition of AR and c-Met oncogenic pathways can prevent or delay CRPC development. This timely study seeks to break new ground and change current paradigms for the treatment of advanced prostate cancer. Data generated from this study should provide critical and necessary scientific evidence for clinical intervention of lethal CRPC to improve survival rates for hundreds of thousands of men.