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

 描述(申请人提供)：最近FDA批准的抑制剂苯扎鲁胺和醋酸阿比特龙已经实现了有效的雄激素剥夺疗法，对前列腺癌男性患者的生存有显着的好处。然而，雄激素受体信号通路的有效抑制剂的长期临床应用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帽。这种耐药表型反过来可能是临床上继续观察到的侵袭性软组织转移增加趋势的原因。这一假说仍然存在争议，需要严格的临床前建模来评估完全抑制雄激素受体信号是否仍然有益，或者它是否会导致患者出现侵袭性的神经内分泌表型。我们的长期目标是确定何时以及有多少雄激素受体抑制是必要的，以防止前列腺癌的进展，同时防止耐药表型的发展。我们的目标是获得预后数据集，以确定遗传上易患t-NECAP的患者，以及可能有助于t-NE帽患者治疗的信号。其目的是提供治疗和基于遗传学的证据，证明有效的雄激素受体信号阻断是t-NECAP的原因，建立临床前模型，概括在人类NE帽队列中发现的关键基因改变，并确定一个潜在的起源细胞(S)用于治疗诱发的NE帽。我们的中心假设是，雄激素受体信号通路的抑制通过干细胞-祖细胞的转分化导致神经内分泌前列腺癌。我们将通过以下相互关联的具体目标来检验这些假设并解决这一临床问题：1.建立慢性雄激素剥夺治疗对神经内分泌前列腺癌进展的影响。我们将应用治疗和基因技术，结合新的报告分析，确定雄激素受体信号的有效抑制对去甲肾上腺素帽表型的影响。2.确定REST是否是与Enza协同促进NE帽的关键遗传开关。使用基因工程小鼠模型，我们将模拟在人类NE帽队列中观察到的频繁的休息丧失，以寻找将前列腺上皮重新编程为神经内分泌谱系的可能性。我们将把我们的模型中的分子签名与NE CAP的临床数据集交叉引用。3.通过干/祖细胞的转分化，评估治疗诱导去甲肾上腺素(NE)帽积聚的可能性。我们将确定具有已知干祖细胞特性的前列腺上皮是否可以启动一个治疗驱动的向NE帽表型反式分化的过程。

 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.