"DNMT and TET1 reprogramming as a targetable mechanism of resistance in advanced prostate cancer"

项目摘要/摘要 前列腺癌是一种由雄激素引起的疾病，因此雄激素受体(AR)靶向治疗 一直是前列腺癌治疗的主要焦点。世系 输掉 机制 AR阳性前列腺癌的癌组织学转化 AR阴性的小细胞癌表达神经内分泌标记物，通常被称为 神经内分泌前列腺癌(NEPC)。NEPC临床上具有侵袭性，预后差。因此， 对NEPC患者的有效治疗仍然是一个未得到满足的临床需求。对分子生物学的透彻理解 开发这种致命疾病的有效治疗方法需要NEPC进展。虽然NEPC 肿瘤无性系起源于前列腺癌，具有共同的基因组改变，有显著的 转化过程中的表观遗传去调控。然而，从机械上讲，我们仍然不知道如何 这些表观遗传改变的出现以及如何最好地利用这些改变作为治疗机会。我们的 来自体内、体外和体外模型的初步和已发表的数据(NEPC患者衍生的有机化合物) 提示N-Myc转录组和Cystrome是雄激素依赖的，并推动上皮细胞的可塑性和 临床相关的NEPC分子程序的获取和表观基因组的重新编程。多数 最近，基于一种新的基因工程小鼠模型(GEMS)的数据，我们发现N-Myc诱导 与RB1缺失协同作用，解除对DNA甲基化读取器、写入器(例如DNMT1和Dnmt3b)和 擦除(例如TET1)。有趣的是，我们和其他人已经证明了特定的分子或药理学 干预可以将NEPC表型逆转为腔状腺癌--临床上更容易处理 表型。我们的总体假设是基于我们已公布的和初步的数据，是具体的 前列腺癌细胞的分子改变(如MYCN诱导/RB1缺失)通过 表观遗传重编程(即DNA甲基化)作为抗AR治疗耐药的机制 导致向NEPC转型。为了解决这一假设，我们将使用患者衍生的有机化合物和 异种移植和新型基因工程小鼠模型阐明DNMTS/TET1的作用和特异性 在建立与NEPC相关的DNA甲基化计划(目标1)时，表征 DNMTs在非小细胞肺癌进展过程中的表达(目标2)及评估DNMTs的治疗潜力 单独或联合AR靶向治疗阻止向NEPC过渡或维持NEPC (目标3)。这些目标的成功实现将为NEPC的发展提供独特的见解，确定关键 和潜在的家族可塑性的靶向介质，并为未来的临床策略提供靶向的理论基础 从前列腺癌向NEPC转变的潜在表观遗传学机制。 可塑性，分化细胞的过程 他们的身份和获得替代世系计划，最近已被确定为一个新兴的 包括前列腺癌在内的几种癌症对靶向治疗的耐药性 这种可塑性可以表现为 。为

Project Summary/Abstract Prostate cancer arises as an androgen driven disease and therefore androgen receptor (AR) targeting therapies have been a major focus of prostate cancer treatment. Lineage lose mechanism cancer histologic transformation from an AR-positive prostate adenocarcinoma to an AR-negative small cell carcinoma that expresses neuroendocrine markers, often referred to as neuroendocrine prostate cancer (NEPC). NEPC is clinically aggressive and prognosis is poor. Therefore, effective treatment for NEPC patients remains an unmet clinical need. A thorough molecular understanding of NEPC progression is needed for the development of effective treatments for this lethal disease. Although NEPC tumors arise clonally from prostate adenocarcinoma and share genomic alterations, there is significant epigenetic deregulation during the transformation process. However, mechanistically, we still do not know how these epigenetic alterations arise and how best to leverage these alterations as a therapeutic opportunity. Our preliminary and published data from in vivo, in vitro and ex vivo models (NEPC-patient-derived organoids) suggest that the N-Myc transcriptome and cistrome is androgen-dependent and drives epithelial plasticity and the acquisition of clinically-relevant, NEPC molecular program and a reprogramming of the epigenome. Most recently, based on data from a new genetically engineered mouse model (GEMs), we found that N-Myc induction synergizes with RB1 loss to deregulate DNA methylation readers, writers (e.g. DNMT1 and DNMT3B) and erasures (e.g. TET1). Interestingly, we and others have shown that specific molecular or pharmacological interventions can revert NEPC phenotype to a luminal—more clinically manageable—adenocarcinoma phenotype. Our over-arching hypothesis, which is based on our published and preliminary data, is that specific molecular alterations (e.g. MYCN induction/RB1 loss) in prostate cancer cells drive lineage plasticity through epigenetic reprogramming (i.e., DNA methylation) as a mechanism of resistance to anti-AR therapy and this leads to transformation to NEPC. To address this hypothesis, we will employ patient-derived organoids and xenograft and novel genetically engineered mouse models to elucidate the role and specificity of DNMTs/TET1 in establishing the NEPC-related DNA methylation program (Aim 1), characterize the upstream regulation of DNMTs expression in the progression to NEPC (Aim 2) and to assess the therapeutic potential of DNMTs inhibition alone or in combination with AR targeted therapy to block the transition to or maintenance of NEPC (Aim 3). Successful completion of these Aims will provide unique insights into NEPC development, identify key and potential targetable mediators of lineage plasticity, and provide rationale for future clinical strategies to target the underlying epigenetic mechanisms that drive the transition from prostate adenocarcinoma to NEPC. plasticity, a process by which differentiated cells their identity and acquire alternative lineage programs, has recently been identified as an emerging of resistance to targeted therapies in several cancer types including prostate cancer prostate this plasticity can manifest as . For