Teply Benjamin A, Antonarakis Emmanuel S
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Curr Opin Endocrinol Diabetes Obes. 2016 Jun;23(3):279-90. doi: 10.1097/MED.0000000000000254.
Understanding the mechanisms by which castration-resistant prostate cancer (CRPC) progresses provides an opportunity to identify novel therapeutic strategies to treat this disease. This understanding has led to approaches to attack prostate cancer's androgen axis in unique ways. This review will examine the classes of novel therapies for androgen axis blockade in CRPC, with a particular focus on the unique characteristics of drugs in various stages of clinical development.
The success of abiraterone and enzalutamide has stimulated multiple investigations into novel approaches to attack the androgen-signaling pathway. Drugs under development include cytochrome P17 inhibitors with 17,20-lyase specificity, androgen receptor antagonists that are active against mutated and constitutively active splice variant forms of the protein, androgen receptor degraders, and bromodomain/bromodomain extra-terminal inhibitors that prevent chromatin binding of activated receptors. The clinical development of several of these experimental agents is reviewed.
Given the unique mechanisms of action for drugs in development, and the possibility that the novel agents may be active in the setting of common resistance mechanisms, treatment options for patients are likely to expand greatly in the coming years. Future studies should prioritize combinations of agents with unique mechanisms of action to optimize outcomes for patients, and should rely on precision-medicine approaches to target known molecular alterations.
了解去势抵抗性前列腺癌（CRPC）进展的机制为确定治疗该疾病的新治疗策略提供了机会。这种认识促使人们以独特的方式攻击前列腺癌的雄激素轴。本综述将研究CRPC中雄激素轴阻断的新型治疗方法类别，特别关注处于临床开发各个阶段的药物的独特特性。
阿比特龙和恩杂鲁胺的成功激发了对攻击雄激素信号通路新方法的多项研究。正在开发的药物包括具有17,20-裂解酶特异性的细胞色素P17抑制剂、对该蛋白的突变和组成型活性剪接变体形式有活性的雄激素受体拮抗剂、雄激素受体降解剂以及阻止活化受体与染色质结合的溴结构域/溴结构域额外末端抑制剂。对其中几种实验药物的临床开发进行了综述。
鉴于正在开发的药物具有独特的作用机制，并且新型药物可能在常见耐药机制的情况下具有活性，未来几年患者的治疗选择可能会大幅增加。未来的研究应优先考虑具有独特作用机制的药物组合，以优化患者的治疗效果，并应依靠精准医学方法来针对已知的分子改变。
