Chronic inhibition of androgen receptor signaling leads to neuroendocrine prostate cancer by trans differentiation of stem/progenitor cells

 描述（由申请方提供）：最近FDA批准的抑制剂Enzalutamide和醋酸阿比特龙已实现有效的雄激素剥夺治疗，对前列腺癌男性患者产生显著的生存获益。然而，长期临床使用雄激素受体信号传导的强效抑制剂也可能产生耐药表型，包括治疗相关的神经内分泌前列腺或t-NE CaP。这种耐药表型可能是临床上持续观察到的侵袭性软组织转移趋势增加的原因。这一假说仍然存在争议，需要严格的临床前建模，以评估雄激素受体信号传导的完全抑制是否仍然有益，或者是否会导致患者的侵袭性神经内分泌表型。 我们的长期目标是确定雄激素受体抑制剂在预防前列腺癌进展同时预防耐药表型发展的时间和程度。我们的目标是获得预后数据集，以确定患者的基因倾向于发展t-NECaP以及签名，可以促进治疗的患者谁获得t-NE CaP。 目的是提供有效雄激素受体信号传导阻断是t-NECaP的原因的治疗和遗传基础证据，开发重现人NE CaP队列中发现的关键遗传改变的临床前模型，并确定治疗诱导的NE CaP的潜在来源细胞。我们的中心假设是雄激素受体信号通路的抑制通过干祖细胞的转分化导致神经内分泌前列腺癌。我们将测试这些假设，并通过以下相关的具体目标来解决这个临床问题：1。确定慢性雄激素剥夺治疗对神经内分泌前列腺癌进展的影响。我们将应用治疗和遗传技术与新的报告分析合作，以确定有效抑制雄激素受体信号对NE CaP表型的影响。 2.确定REST是否是与ENZA合作促进NE CaP的关键遗传开关。使用基因工程小鼠模型，我们将模拟在人NE CaP队列中观察到的REST的频繁丢失，以获得将前列腺上皮细胞重编程为神经内分泌谱系的潜力。我们将交叉引用来自我们的模型的分子特征与NE CaP的临床数据集。 3.评价通过干/祖细胞的转分化治疗诱导NE CaP蓄积的潜力。我们将确定具有已知干-祖细胞品质的前列腺上皮是否可以启动治疗驱动的向NE CaP表型的转分化过程。

 DESCRIPTION (provided by applicant): Potent androgen deprivation therapy has been achieved with the recently FDA approved inhibitors enzalutamide and abiraterone acetate resulting in significant survival benefits for men with prostate cancer. However, the prolonged clinical use of potent inhibitors of androgen receptor signaling may also be yielding resistance phenotypes including treatment related neuroendocrine prostate or t-NE CaP. This resistance phenotype may be, in turn, a cause for the increasing trend of aggressive, soft tissue metastasis that continues to be observed in the clinic. This hypothesis remains controversial and requires rigorous pre-clinical modeling to evaluate whether complete suppression of androgen receptor signaling remains beneficial or whether it is leading to an aggressive, neuroendocrine phenotype in patients. Our long-term goal is to ascertain when and how much androgen receptor inhibition is necessary to prevent prostate cancer progression while preventing the development of resistance phenotypes. We aim to obtain prognostic data sets to identify patients that are genetically predisposed to developing t- NECaP as well as signatures that may facilitate treatment for patients who have acquired t-NE CaP. The objective is to provide treatment and genetic based evidence that potent androgen receptor signaling blockade is a cause of t-NECaP, develop preclinical models recapitulating key genetic alterations found in human NE CaP cohorts and determine a potential cell(s) of origin for treatment induced NE CaP. Our central hypothesis is that suppression of the androgen receptor signaling pathway leads to neuroendocrine prostate cancer through trans differentiation of stem-progenitor cells. We will test these hypotheses and address this clinical problem by the following interrelated Specific Aims: 1. Establish the impact of chronic androgen deprivation treatment on neuroendocrine prostate cancer progression. We will apply therapies and genetic techniques in collaboration with novel reporter assays to determine the impact of potent suppression of androgen receptor signaling on NE CaP phenotypes. 2. Determine if REST is a critical genetic switch that cooperates with ENZA to promote NE CaP. Using genetically engineered mouse models we will model the frequent loss of REST, observed in human NE CaP cohorts, for potential to reprogram prostate epithelium to a neuroendocrine lineage. We will cross reference molecular signatures from our models with clinical data sets for NE CaP. 3. Evaluate the potential for therapy-induced accumulation of NE CaP through trans differentiation of stem/progenitor cells. We will determine whether prostate epithelium with known stem- progenitor qualities can initiate a process of therapy driven trans differentiation towards NE CaP phenotype.