NOTCH signaling controls transformation to androgen independent neuroendocrine prostate cancer

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)。新生儿猝死的发病率 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。这表明日益严格的AR信号封锁正在推动 NEPC。这是一个重要的临床问题，因为NEPC是侵袭性和致命性的；开发有效的 由于对相关分子机制的了解有限，治疗受到阻碍。NEPC显然产生于 ARPOS CRPC在同时携带两者的患者中具有共同的克隆性起源。我们已经确定了基因 Rb1/Trp53抑癌基因的失活协同促进ARPOS PADC向 NEPC通过去抑制表观遗传重编程因子。抑制这些重新编程因素 逆转NEPC转化并恢复ADT敏感性，证明表观遗传变化是 牵涉其中。我们假设Noch-ASCL1信号的改变触发了表观遗传学 对潜在的NEPC转换进行重新编程。这一假说作为一种途径具有临床意义。 可以在治疗上被操纵以延迟或逆转NEPC转变，延长 某些患者ADT临床有效反应的持续时间。我们利用小说提出了三个具体目标 前列腺癌小鼠模型和独特的人类临床标本来验证这一假设，表征如何 PADC细胞转化为NEPC细胞，探索新的治疗方法 致命的前列腺癌。我们将：1)测试Noch信号是否足以维持雄激素 依赖的PADC表型；2)前列腺癌细胞如何从PADC向NEPC转化；3) 表观调控药物是否逆转NEPC转化和ADT耐药 Noch-ASCL1信令。该项目的长期目标是通过以下方式改善前列腺癌的治疗 促进对谱系可塑性作为获得性治疗抵抗机制的机制的理解。

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 NEPC variants among CRPC 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. This is an important clinical problem because NEPC is aggressive and lethal; 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 that a change in NOTCH-ASCL1 signaling triggers the epigenetic reprogramming underlying NEPC transformation. 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. We propose three specific aims using novel prostate cancer mouse models and unique human clinical specimens to test this hypothesis, characterize how PADC cells transform into NEPC cells, and explore novel therapeutic approaches for the treatment of this lethal form of prostate cancer. We will: 1) Test if NOTCH signaling is sufficient to maintain an androgen dependent PADC phenotype; 2) Characterize how prostate cancer cells transition from PADC to NEPC; 3) Determine whether epigenetic modulating drugs reverse NEPC transformation and ADT resistance via NOTCH-ASCL1 signaling. The long term goal of this project is to improve prostate cancer therapy by advancing mechanistic understanding of lineage plasticity as a mechanism of acquired therapeutic resistance.