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.

摘要 雄激素剥夺疗法(ADT)对转移性前列腺癌(PADC)有效，但所有 患者不可避免地复发，患有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，但有相当一部分缺乏AR表达，成为AR信号 独立并异常表达神经内分泌谱系标记物(NEPC)。这些NEPC的发生率 随着更多的患者受益于改善的ADT，如苯扎鲁胺和醋酸阿比特龙，变异药物的数量也增加了。 这表明，越来越严格的AR信号封锁正在推动NEPC的发展。NEPC咄咄逼人 而且是致命的，因此反映了一个日益严重的临床问题。有效疗法的开发因有限而受阻 了解相关的分子机制。NEPC显然起源于ARpos CRPC，因为它们共享克隆 起源于两者都有的患者。我们已经确定RB1/Trp53肿瘤的遗传失活 抑制基因协同作用促进ARPOS PADC向NEPC的转化 表观遗传重编程因素。抑制这些重新编程因素会逆转NEPC转换和 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潜在的NEPC的表观遗传重编程 转分化。这一假设具有临床后果，因为可以想象，这种途径可能是 通过治疗手段延缓或逆转NEPC转化，延长受益ADT的持续时间 部分患者出现临床反应。此管理多样性补充应用程序旨在支持 毛里西奥·弗洛雷斯，博士前学生，将参与家长R01资助的研究项目 研究Notch信号在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)确定足以支持的有机培养条件 2)检测Notch信号对体外培养的NEPC转分化的影响； 确定在体外影响NEPC转分化的间质-癌细胞相互作用。的长期目标是 这一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和改善前列腺癌 通过促进对谱系可塑性作为获得性机制的机制的理解进行癌症治疗 治疗抵抗力。