Berruti Alfredo, Dalla Volta Alberto
Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, Medical Oncology, University of Brescia at ASST-Spedali Civili, Brescia, Italy.
Oncologia Medica, ASST-Spedali Civili, Piazzale Spedali Civili 1, 25123, Brescia, Italy.
Handb Exp Pharmacol. 2018;249:181-194. doi: 10.1007/164_2017_21.
Several therapeutic strategies are actually available in the management of prostate cancer: Targeting the androgen receptor (AR) is the goal both for initial androgen deprivation therapy (ADT) and second-generation androgen ablative agents (abiraterone and enzalutamide). Chemotherapy with taxanes, administered upon progression or as first line approach in association with ADT, is another therapeutic option. Unfortunately, none of these therapies is curative and patients are destined to develop a resistant phenotype.Progression to ADT leads to the attainment of a castration resistant disease whose mechanisms remain incompletely understood. Reactivation of AR has been shown to occur and second-generation of AR targeting drugs are usually prescribed. Upon progression to these agents AR signaling still remains the primary driver although it often becomes ligand independent, since it can be either restored through mutations on the ligand binding domain and/or formation of AR splicing variants or by passed through a cross talk with other oncogenic signaling pathways.AR-independent signaling pathways may represent additional mechanisms underlying castration resistant progression. It is clear that castration resistant prostate cancer is a group of diverse diseases and new treatment paradigms need to be developed.
在前列腺癌的治疗中，实际上有几种治疗策略：靶向雄激素受体（AR）是初始雄激素剥夺疗法（ADT）和第二代雄激素消融剂（阿比特龙和恩杂鲁胺）的目标。在疾病进展时或作为与ADT联合使用的一线方法给予紫杉烷类化疗是另一种治疗选择。不幸的是，这些疗法都无法治愈，患者注定会产生耐药表型。进展为ADT会导致去势抵抗性疾病的出现，其机制仍未完全了解。已证明AR会重新激活，通常会开具第二代AR靶向药物。在进展到这些药物后，AR信号传导仍然是主要驱动因素，尽管它通常变得不依赖配体，因为它可以通过配体结合域的突变和/或AR剪接变体的形成来恢复，或者通过与其他致癌信号通路的串扰来实现。不依赖AR的信号通路可能代表去势抵抗性进展的其他机制。显然，去势抵抗性前列腺癌是一组多样化的疾病，需要开发新的治疗模式。
