Resistance to Emerging Androgen Deprivation Therapies in Prostate Cancer

描述（由申请人提供）：对于转移性去势抵抗性前列腺癌，最近的进展导致了“第二代”ADT （ADT2）疗法的部署，包括靶向雄激素生物合成成分的醋酸阿比特龙（AA）和直接靶向雄激素受体的恩杂鲁胺。AA和enzalutamide都证明了转移性CRPC患者的总体生存获益；然而，大多数患者仍然对这些药物产生耐药性，从而导致前列腺癌相关的发病率和死亡率。最近已经确定了几种ADT2耐药机制，尽管ADT2耐药机制的总体谱仍然不完整，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以在ADT2方案中推广或在特定的治疗环境中起作用仍然未知。最后，除了使用细胞毒性化疗（如紫杉烷）之外，该患者群体的后续治疗选择尚未明确。本提案的目标是创建和应用计算生物学算法，1)系统地询问ADT2在临床相关时间点的基因组抗性效应；

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.