NOTCH signaling controls transformation to androgen independent neuroendocrine prostate cancer

NOTCH信号控制向雄激素非依赖性神经内分泌前列腺癌的转化

• 批准号: 10346091
• 负责人: DAVID W. GOODRICH
• 金额: $ 4.86万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-22 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10346091
• 关键词: Acetates; Affect; Androgen Receptor; Androgens; Automobile Driving; Cell Communication; Clinical; DNA Sequence Alteration; Development; Development Plans; Epigenetic Process; Genetic; Goals; Grant; In Vitro; Incidence; Malignant Neoplasms; Malignant neoplasm of prostate; Mentors; Metastatic Prostate Cancer; Molecular; Neuroendocrine Prostate Cancer; Neurosecretory Systems; Organoids; Parents; Pathway interactions; Patients; Phenotype; Prostate Adenocarcinoma; Prostate Cancer therapy; RB1 gene; Receptor Signaling; Relapse; Research; Research Support; Role; Signal Transduction; Students; TP53 gene; Testing; Therapeutic; Tumor Suppressor Genes; Variant; abiraterone; androgen deprivation therapy; androgen independent prostate cancer; androgen sensitive; anticancer research; cancer cell; career development; castration resistant prostate cancer; derepression; effective therapy; improved; molecular targeted therapies; notch protein; novel strategies; pre-doctoral; programs; receptor expression; response; therapy resistant; transdifferentiation; tumor microenvironment

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.

概括 雄激素剥夺疗法（ADT）可有效治疗转移性前列腺癌（PADC），但所有 去势抵抗性前列腺癌（CRPC）患者不可避免地会复发。大多数 CRPC 仍依赖于 雄激素受体 (AR) 信号传导，但很大一部分缺乏 AR 表达，成为 AR 信号传导 独立且异常表达的神经内分泌谱系标记物（NEPC）。这些 NEPC 的发生率 随着越来越多的患者受益于改进的 ADT（如恩杂鲁胺和醋酸阿比特龙），变体也随之增加。 这表明日益严格的 AR 信号封锁正在推动 NEPC 的发展。 NEPC 积极进取 和致命的，从而反映了一个日益严重的临床问题。有效疗法的开发受到有限的阻碍 了解相关的分子机制。 NEPC 显然源自 ARpos CRPC，因为它们共享克隆 起源于同时具有这两种情况的患者。我们已经确定 RB1/TRP53 肿瘤的基因失活 抑制基因合作通过去抑制来促进 ARpos PADC 向 NEPC 的转化 表观遗传重编程因子。抑制这些重编程因子可逆转 NEPC 转化并 恢复 ADT 敏感性，表明涉及表观遗传变化。我们假设Notch信号传导 肿瘤微环境中抑制 NEPC 的表观遗传重编程 转分化。这一假设具有临床影响，因为该途径可能是 通过治疗手段延迟或逆转 NEPC 转化，延长有益 ADT 的持续时间 一些患者的临床反应。提出此行政多样性补充申请是为了支持 Mauricio Flores，博士前学生，将参与家长 R01 补助金支持的研究计划 描述 NOTCH 信号在 NEPC 转分化中的作用。研究、指导和职业 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 NEPC体外转分化； 2）体外测试Notch信号如何影响NEPC转分化； 3） 确定影响体外 NEPC 转分化的基质-癌细胞相互作用。长期目标是 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机制的机制理解来治疗癌症 治疗抵抗。