Co-targeting oncogenic pathways in advanced prostate cancer

 描述(申请人提供)：前列腺癌是北美男性最常见的非皮肤病恶性肿瘤。虽然筛查和早期发现降低了死亡率，但仍没有针对晚期疾病的根治疗法。因此，所有患有去势抵抗肿瘤的患者最终都会死于他们的疾病。因此，开发一种有效的治疗晚期前列腺癌的方法是一个重要的未得到满足的临床需求。通过针对两条重要的致癌途径，我们已经确定了一种联合疗法，可以杀死去势抵抗的前列腺癌。值得注意的是，虽然许多(失败的)靶向治疗被证明可以减缓前列腺癌的生长，但在几个模型中，这种药物组合实际上导致了体内肿瘤的坦率消退。该项目的目标是解构这些药物发挥作用的机制，利用这一洞察力来确定最佳药物/靶点，并在患者来源的异种移植(PDX)模型中验证这些药物的治疗效果。这将通过细胞、表观遗传学和基因组学方法以及通过在体内进行额外的临床前研究来实现。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，而且还将揭示杀死耐去势前列腺癌的机制，这最终可能导致其他治疗策略的开发。

 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.