A novel targetable mechanism for castration-resistant prostate cancer

项目摘要 前列腺癌是老年癌症患者中最常见的癌症， 每年有13，000名退伍军人被诊断患有前列腺癌。去势抵抗性前列腺癌（CRPC）是一种 由于对雄激素剥夺疗法产生耐药性而导致的致死型前列腺癌，以及新的 产生抗雄激素药物（即醋酸阿比特龙和Enzalutamide）。因此迫切 需要通过了解导致CRPC的机制来开发治疗CRPC的新方法， 寻找新的治疗靶点 异常的Wnt/β-catenin信号传导在抗雄激素治疗的抵抗和 CRPC。在我们的初步研究中，我们发现Slit/Robo GT3激活蛋白1（srGAP 1）是一种潜在的 CRPC中Wnt靶基因与雄激素受体（AR）信号共调节。此外，我们还发现 Slit/Roundabout（Robo）信号传导的多个组分，包括srGAP 1、Robo 1、Slit 2和RhoA， 与原发性PCa相比，在CRPC中扩增并过表达。 反之亦然，Slit/Robo信号可以通过促进细胞核内蛋白质的表达来激活Wnt/β-catenin信号。 通过Rac 1激活定位β-连环蛋白。我们还发现srGAP 1与鸟嘌呤相互作用， 癌基因Vav 2/Vav 3的核苷酸交换因子（GEF）家族，已知其调节细胞核内的 雄激素受体变体7（AR V7和全长AR）和CRPC细胞的存活。基于这些 根据观察，我们假设srGAP 1通过相互作用在CRPC的进展中起关键作用。 AR和Wnt信号的扩增。 为了检验这些假设，我们将首先检验srGAP 1是一种必需的下调- 导致进展为CRPC和对抗雄激素治疗耐药的中间体。二是 评估srGAP 1对AR和Wnt/β-连环蛋白信号传导以及对 CRPC的生物学行为。第三，我们将确定病理生理相关性的相互作用， Slit/Robo/srGAP 1、AR和Wnt信号传导以及srGAP 1的表达是否将是AR和Wnt信号传导的良好预测因子。 CRPC患者的疾病进展和总生存期。 我们希望明确srGAP 1在CRPC进展中的作用和机制，这可能导致 确定一个新的目标或预后标志物的管理这种致命的肿瘤。因此，我们认为， 我们建议的工作与VA部门的优先研究领域非常一致-高风险疾病 退伍军人人群的医疗保健负担和专注于个体治疗的精准医学研究 反应

Project Summary Prostate cancer is the most frequently diagnosed cancer among veteran cancer patients with more than 13,000 veterans diagnosed with prostate cancer each year. Castration-resistant prostate cancer (CRPC) is a lethal type of prostate cancer due to developing resistance to androgen deprivation therapy and the new generation of anti-androgen drugs (i.e. Abiraterone Acetate, and Enzalutamide). Therefore, there is an urgent need to develop novel approaches for treatment of CRPC by understanding mechanisms leading to CRPC and identifying new therapeutic targets. Aberrant Wnt/β-catenin signaling plays a critical role in resistance to anti-androgen therapies and in CRPC. In our preliminary studies, we found that Slit/Robo GTPase activating protein 1 (srGAP1) is a potential Wnt target gene and co-regulated by androgen receptor (AR) signaling in CRPC. In addition, we found that multiple components of Slit/Roundabout (Robo) signaling, including srGAP1, Robo1, Slit2 and RhoA, are amplified and overexpressed in CRPC compared to primary PCa. Vice versa, Slit/Robo signaling can activate Wnt/β-catenin signaling by promoting the nuclear localization of β-catenin via Rac1 activation. We have also discovered that srGAP1 interacts with guanine nucleotide exchange factor (GEF) family of oncogenes Vav2/Vav3 that are known to regulate nuclear levels of androgen receptor variant 7 (AR V7 and full-length AR) and the survival of CRPC cells. Based these observations, we hypothesize that srGAP1 plays a critical role in progression to CRPC through reciprocal amplification of both AR and Wnt signaling. To test these hypotheses, we will first test the hypothesis that srGAP1 is one of the required down- stream intermediates for progression to CRPC and for resistance to anti-androgen therapies. Second, we will assess the functional and mechanistic importance of srGAP1 on AR and Wnt/-catenin signaling and on biological behaviors of CRPC. Third, we will determine pathophysiological relevance of the interplay between Slit/Robo/srGAP1, AR and Wnt signaling and whether the expression of srGAP1 will be a good predictor for disease progression and overall survival of CRPC patients. We expect to define the role and mechanisms of srGAP1 in progression to CRPC, which may lead to identification of a novel target or prognostic markers for the management of this deadly neoplasm. Therefore, our proposed work aligns very well with priority research areas of the Department of VA---Diseases with a high healthcare burden in the Veteran population and Precision medicine studies focused on individual treatment response.