Resistance to Emerging Androgen Deprivation Therapies in Prostate Cancer

描述(申请人提供)：对于耐去势转移性前列腺癌，最近的进展已导致部署“第二代”ADT(ADT2)疗法，包括以雄激素生物合成的一种成分为靶点的醋酸阿比特龙(AA)，以及直接以雄激素受体为靶点的苯扎鲁胺。AA和苯扎鲁胺在转移性CRPC患者中都显示出总体的生存益处；然而，大多数患者仍然对这些药物产生耐药性，这导致了前列腺癌相关的发病率和死亡率。最近已经发现了几种对ADT2耐药的机制，尽管对ADT2耐药机制的总体谱仍未完全确定，这些事件的生物学影响也是如此。此外，这种机制在多大程度上可能在ADT2方案中推广或在特定的治疗环境中发挥作用仍是未知的。最后，除了使用细胞毒性化疗药物(例如紫杉烷)外，该患者群体的后续治疗选择并未得到很好的定义。这项建议的目标是创建和应用计算生物学算法，该算法1)在临床相关的时间点系统地询问基因组对ADT2的抗性效应， 2)将ADT2耐药的体外模型与基因组特征相结合，定义与ADT2耐药密切相关的生物模块；3)用基因组数据建立临床耐药模型，以指导后续的治疗策略。通过这样做，我们的目标是发现临床ADT2耐药的新模块，为ADT2耐药患者提供合理治疗方法的扩展提供洞察力，并创建一个推断框架，通过该框架，临床医生可能最终根据肿瘤基因组图谱预测最有可能使个体患者受益的治疗策略。这些努力将有助于在新的佐剂和转移性CRPC环境中集中和全面地评估ADT2耐药性，解释前列腺癌对ADT2的遗传耐药性，并确定后续的治疗策略。

DESCRIPTION (provided by applicant): For metastatic castration resistant prostate cancer, recent advances have led to the deployment of "second- generation" ADT (ADT2) therapies, including abiraterone acetate (AA), which targets a component of androgen biosynthesis, and enzalutamide, which targets the androgen receptor directly. Both AA and enzalutamide have demonstrated an overall survival benefit in patients with metastatic CRPC; however, most patients still develop resistance to these agents, which drives prostate cancer-associated morbidity and mortality. Several mechanisms of resistance to ADT2 have recently been identified, although the overall spectrum of resistance mechanisms to ADT2 remains incompletely characterized, as does the biological impact of these events. Moreover, the extent to which such mechanisms might generalize across ADT2 regimens or operate in specific therapeutic contexts remains unknown. Finally, subsequent treatment options for this patient population beyond the use of cytotoxic chemotherapies (e.g. taxanes) are not well defined. The goal of this proposal is to create and apply computational biology algorithms that 1) systematically interrogate genomic resistance effectors to ADT2 in clinically relevant time points, 2) integrate in vitro models of ADT2 resistance with genomic features to define biological modules germane to ADT2 resistance, and 3) model clinical resistance with genomic data to inform subsequent treatment strategies. In doing so, we aim to discover new modules for clinical ADT2 resistance, provide insight into the expansion of rational treatment approaches for ADT2-resistant patients, and create an inferential framework through which clinicians may ultimately predict those treatment strategies most likely to benefit individual patients based on tumor genomic profiles. These efforts will facilitate a focused and comprehensive assessment of ADT2 resistance in the neoadjuvant and metastatic CRPC settings, explain genetic resistance to ADT2 in prostate cancer, and define subsequent therapeutic strategies.