NOTCH signaling controls transformation to androgen independent neuroendocrine prostate cancer

总结 雄激素剥夺疗法（ADT）治疗转移性前列腺癌（PADC）有效，但所有 患者不可避免地复发去势抵抗性前列腺癌（CRPC）。大多数CRPC仍然依赖于 雄激素受体（AR）信号传导，但显著部分缺乏AR表达，成为AR信号传导 独立和异常表达的神经内分泌谱系标志物（NEPC）。这些NEPC的发生率 随着更多患者从改善的ADT（如enzalutamide和醋酸阿比特龙）中获益，变异增加。 这表明越来越严格的AR信号阻断正在推动NEPC的发展。NEPC具有侵略性 并且致命，因此反映了日益严重的临床问题。有效疗法的开发受到有限的 了解相关的分子机制。NEPC明显来自ARpos CRPC，因为它们共享克隆 两者都有的病人。我们已经确定RB 1/TRP 53肿瘤的基因失活 抑制基因协同促进ARpos PADC转化为NEPC， 表观遗传重编程因子抑制这些重编程因子逆转NEPC转化， 恢复ADT敏感性，表明涉及表观遗传变化。我们假设Notch信号 在肿瘤微环境中抑制NEPC的表观遗传重编程 转分化这一假设具有临床分支，因为可以想象， 在治疗上进行操作以延迟或逆转NEPC转化，延长有益ADT的持续时间 一些患者的临床反应。本行政多样性补充申请旨在支持 Mauricio弗洛雷斯，一名博士前学生，将参与父母R 01资助的研究项目 表征NOTCH信号传导在NEPC转分化中的作用。研究、指导和职业生涯 发展计划提出了三个研究目标：1）确定足以支持的类器官培养条件 2）测试Notch信号传导如何影响体外NEPC转分化; 3） 鉴定影响体外NEPC转分化的基质-癌细胞相互作用。的长期目标 这种多样性补充是为了促进弗洛雷斯先生的癌症研究事业发展，并改善前列腺 通过推进对谱系可塑性作为获得性免疫调节机制的机制理解， 治疗抵抗

Summary Androgen deprivation therapy (ADT) is effective in treating metastatic prostate adenocarcinoma (PADC), but all patients inevitably relapse with castrate resistant prostate cancer (CRPC). Most CRPCs remain dependent on androgen receptor (AR) signaling, but a significant fraction lack AR expression, become AR signaling independent, and aberrantly express neuroendocrine lineage markers (NEPC). The incidence of these NEPC variants has increased as more patients benefit from improved ADTs like enzalutamide and abiraterone acetate. This suggests increasingly stringent AR signaling blockade is driving development of NEPC. NEPC is aggressive and lethal, thus reflecting a growing clinical problem. Development of effective therapies is hampered by limited understanding of relevant molecular mechanisms. NEPC clearly arises from ARpos CRPC as they share clonal origin in patients that harbor both. We have determined that genetic inactivation of the RB1/TRP53 tumor suppressor genes cooperate to facilitate transformation of ARpos PADC to NEPC through derepression of epigenetic reprogramming factors. Inhibiting these reprogramming factors reverses NEPC transformation and restores ADT sensitivity, demonstrating that epigenetic changes are involved. We hypothesize Notch signaling within the tumor microenvironment suppresses the epigenetic reprogramming underlying NEPC transdifferentiation. This hypothesis has clinical ramifications as the pathway could conceivably be manipulated therapeutically to delay or reverse NEPC transformation, extending the duration of beneficial ADT clinical responses in some patients. This administrative diversity supplement application is proposed to support Mauricio Flores, a predoctoral student who will be involved in the parent R01 grant supported research program characterizing the role of NOTCH signaling in NEPC transdifferentiation. The research, mentoring, and career development plan proposes three research aims: 1) Identify organoid culture conditions sufficient to support NEPC transdifferentiation in vitro; 2) Test how Notch signaling affects NEPC transdifferentiation in vitro; 3) Identify stromal-cancer cell interactions that influence NEPC transdifferentiation in vitro. The long-term goal of this diversity supplement is to facilitate Mr. Flores' cancer research career development and to improve prostate cancer therapy by advancing mechanistic understanding of lineage plasticity as a mechanism of acquired therapeutic resistance.