A major hurdle in the study of rare tumors is a lack of existing preclinical models. Neuroendocrine prostate cancer is an uncommon and aggressive histologic variant of prostate cancer that may arise de novo or as a mechanism of treatment resistance in patients with pre-existing castration-resistant prostate cancer. There are few available models to study neuroendocrine prostate cancer. Here, we report the generation and characterization of tumor organoids derived from needle biopsies of metastatic lesions from four patients. We demonstrate genomic, transcriptomic, and epigenomic concordance between organoids and their corresponding patient tumors. We utilize these organoids to understand the biologic role of the epigenetic modifier EZH2 in driving molecular programs associated with neuroendocrine prostate cancer progression. High-throughput organoid drug screening nominated single agents and drug combinations suggesting repurposing opportunities. This proof of principle study represents a strategy for the study of rare cancer phenotypes.

中文翻译：

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源自患者的类器官可模拟罕见的前列腺癌表型。


罕见肿瘤研究的一个主要障碍是缺乏现有的临床前模型。神经内分泌前列腺癌是前列腺癌的一种罕见且具有侵袭性的组织学变异，可能是从头出现的，也可能是已有去势抵抗性前列腺癌患者的治疗抵抗机制。用于研究神经内分泌前列腺癌的可用模型很少。在这里，我们报告了从四名患者的转移性病变的针活检中获得的肿瘤类器官的生成和表征。我们证明了类器官与其相应的患者肿瘤之间的基因组、转录组和表观基因组的一致性。我们利用这些类器官来了解表观遗传修饰剂 EZH2 在驱动与神经内分泌前列腺癌进展相关的分子程序中的生物学作用。高通量类器官药物筛选提名了单一药物和药物组合，提示了重新利用的机会。这项原理证明研究代表了研究罕见癌症表型的策略。