Co-targeting oncogenic pathways in advanced prostate cancer

 描述（由申请人提供）：前列腺癌是北美男性中最常见的非皮肤恶性肿瘤。虽然筛查和早期发现降低了死亡率，但仍然没有治愈晚期疾病的治疗方法。因此，所有患有去势抵抗性肿瘤的患者最终都会死于这种疾病。因此，开发用于晚期前列腺癌的有效疗法代表了重要的未满足的临床需求。通过靶向两个重要的致癌途径，我们已经确定了一种联合治疗，杀死去势抵抗性前列腺癌。值得注意的是，虽然许多（失败的）靶向治疗已被证明可以减缓前列腺癌的生长，但这种药物组合实际上在几种模型中导致体内肿瘤明显消退。该项目的目标是解构这些药物发挥作用的机制，利用这种见解来确定最佳药物/靶点，并验证这些药物在患者来源的异种移植物（PDX）模型中的治疗效果。这将通过细胞、表观遗传和基因组方法以及通过进行额外的体内临床前研究来实现。这些研究不仅将提供宝贵的临床前数据来指导临床试验的发展，而且将揭示杀死去势抵抗性前列腺癌的机制，这可能最终导致额外治疗策略的发展。

 DESCRIPTION (provided by applicant): Prostate cancer is the most frequently diagnosed non-dermatological malignancy in North American men. While screening and early detection have reduced mortality, there is still no curative treatment for advanced disease. As such all patients that develop castration-resistant tumors will ultimately die from their disease. Therefore developing an effective therapy for advanced prostate cancer represents an important unmet clinical need. By targeting two important oncogenic pathways we have identified a combination therapy that kills castration-resistant prostate cancer. Notably, while many (failed) targeted therapies have been shown to slow prostate cancer growth, this drug combination actually causes frank tumor regression in vivo in several models. The goal of this project is to deconstruct the mechanism by which these agents function, use this insight to identify the optimal drugs/targets, and validate the therapeutic effects of these agents in patient-derived xenograft (PDX) models. This will be accomplished through cellular, epigenetic, and genomic approaches and by conducting additional preclinical studies in vivo. These studies will not only provide invaluable preclinical data to guide the development of a clinical trial, but will uncover mechanisms that kill castration- resistant prostate cancer, which may ultimately lead to the development of additional therapeutic strategies.