Lineage plasticity and histologic transformation to small cell neuroendocrine prostate cancer (NEPC) is an increasingly recognized mechanism of treatment resistance in advanced prostate cancer. This is associated with aggressive clinical features and poor prognosis. Recent work has identified genomic, epigenomic, and transcriptome changes that distinguish NEPC from prostate adenocarcinoma, pointing to new mechanisms and therapeutic targets. Treatment-related NEPC arises clonally from prostate adenocarcinoma during the course of disease progression, retaining early genomic events and acquiring new molecular features that lead to tumor proliferation independent of androgen receptor activity, and ultimately demonstrating a lineage switch from a luminal prostate cancer phenotype to a small cell neuroendocrine carcinoma. Identifying the subset of prostate tumors most vulnerable to lineage plasticity and developing strategies for earlier detection and intervention for patients with NEPC may ultimately improve prognosis. Clinical trials focused on drug targeting of the lineage plasticity process and/or NEPC will require careful patient selection. Here, we review emerging targets and discuss biomarker considerations that may be informative for the design of future clinical studies.

中文翻译：

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神经内分泌前列腺癌的治疗注意事项：下一步是什么？

小细胞神经内分泌前列腺癌 (NEPC) 的谱系可塑性和组织学转化是晚期前列腺癌治疗耐药性的日益公认的机制。这与侵袭性临床特征和不良预后有关。最近的工作已经确定了区分 NEPC 与前列腺腺癌的基因组、表观基因组和转录组变化，指出了新的机制和治疗靶点。治疗相关的 NEPC 在疾病进展过程中从前列腺腺癌克隆性地产生，保留早期基因组事件并获得导致肿瘤增殖的新分子特征，而与雄激素受体活性无关，并最终证明从管腔前列腺癌表型到小细胞神经内分泌癌。确定最易受谱系可塑性影响的前列腺肿瘤亚群，并制定早期检测和干预 NEPC 患者的策略可能最终改善预后。专注于谱系可塑性过程和/或 NEPC 的药物靶向的临床试验将需要仔细选择患者。在这里，我们回顾了新兴目标并讨论了可能为未来临床研究设计提供信息的生物标志物考虑因素。