Cancer Research UK Manchester Institute Cancer Biomarker Centre, The University of Manchester, Alderley Park, United Kingdom.
Manchester European Neuroendocrine Tumour Society (ENETS) Centre of Excellence, The Christie NHS Foundation Trust, Manchester, United Kingdom.
Clin Cancer Res. 2022 May 13;28(10):1999-2019. doi: 10.1158/1078-0432.CCR-21-3058.
Poorly differentiated neuroendocrine carcinomas (PD-NEC) are rare cancers garnering interest as they become more commonly encountered in the clinic. This is due to improved diagnostic methods and the increasingly observed phenomenon of "NE lineage plasticity," whereby nonneuroendocrine (non-NE) epithelial cancers transition to aggressive NE phenotypes after targeted treatment. Effective treatment options for patients with PD-NEC are challenging for several reasons. This includes a lack of targetable, recurrent molecular drivers, a paucity of patient-relevant preclinical models to study biology and test novel therapeutics, and the absence of validated biomarkers to guide clinical management. Although advances have been made pertaining to molecular subtyping of small cell lung cancer (SCLC), a PD-NEC of lung origin, extrapulmonary (EP)-PD-NECs remain understudied. This review will address emerging SCLC-like, same-organ non-NE cancer-like and tumor-type-agnostic biological vulnerabilities of EP-PD-NECs, with the potential for therapeutic exploitation. The hypotheses surrounding the origin of these cancers and how "NE lineage plasticity" can be leveraged for therapeutic purposes are discussed. SCLC is herein proposed as a paradigm for supporting progress toward precision medicine in EP-PD-NECs. The aim of this review is to provide a thorough portrait of the current knowledge of EP-PD-NEC biology, with a view to informing new avenues for research and future therapeutic opportunities in these cancers of unmet need.
分化差的神经内分泌癌(PD-NEC)较为罕见,但由于诊断方法的改进和越来越多的“神经内分泌系可塑性”现象观察到,即在靶向治疗后,非神经内分泌(非-NE)上皮癌向侵袭性神经内分泌表型转变,因此在临床上更为常见。PD-NEC 患者的有效治疗选择因多种原因而具有挑战性。这包括缺乏可靶向的、复发性分子驱动因素,缺乏用于研究生物学和测试新型治疗方法的患者相关临床前模型,以及缺乏经过验证的生物标志物来指导临床管理。尽管在小细胞肺癌(SCLC)的分子亚分型方面取得了进展,但起源于肺部的 PD-NEC,肺外(EP)-PD-NEC 仍研究不足。这篇综述将探讨新兴的 SCLC 样、同一器官非神经内分泌癌样和肿瘤类型不可知的 EP-PD-NEC 生物学脆弱性,以及潜在的治疗利用。讨论了这些癌症的起源假说以及如何利用“神经内分泌系可塑性”来达到治疗目的。本文提出 SCLC 可以作为支持 EP-PD-NEC 精准医学进展的范例。本综述的目的是全面描绘 EP-PD-NEC 生物学的现有知识,以期为这些未满足需求的癌症的研究和未来治疗机会提供新的途径。