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

项目总结/摘要 前列腺癌是一种雄激素驱动的疾病，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。谱系 失去 机制 从AR阳性前列腺癌到 一种表达神经内分泌标志物的AR阴性小细胞癌，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，我们认为， NEPC患者的有效治疗仍然是未满足的临床需求。从分子水平全面了解 NEPC的进展是开发这种致命疾病的有效治疗所必需的。虽然NEPC 肿瘤从前列腺腺癌克隆产生并共享基因组改变， 转化过程中的表观遗传失调。然而，从机制上讲，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 来自体内、体外和离体模型（NEPC患者源性类器官）的初步和已发表数据 表明N-Myc转录组和顺式组是雄激素依赖性的，并驱动上皮可塑性， 获得临床相关的NEPC分子程序和表观基因组的重编程。最 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丢失协同作用，解除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，我们和其他人已经表明，特定的分子或药理学 干预可以将NEPC表型逆转为临床上更易处理的管腔腺癌 表型。我们的过度兴奋假设是基于我们公布的和初步的数据， 前列腺癌细胞中的分子改变（例如MYCN诱导/RB1丢失）通过以下方式驱动谱系可塑性： 表观遗传重编程（即，DNA甲基化）作为抗AR疗法抗性的机制，并且这 导致向NEPC的转变。为了解决这一假设，我们将采用患者来源的类器官， 异种移植和新型基因工程小鼠模型，以阐明DNMTs/TET1的作用和特异性 在建立NEPC相关的DNA甲基化程序（目标1）时， DNMT在NEPC进展中的表达（目的2），并评估DNMT的治疗潜力 单独抑制或与AR靶向治疗联合，以阻断向NEPC的转变或维持NEPC (Aim 3）。成功完成这些目标将为NEPC的发展提供独特的见解，确定关键的 以及潜在的可靶向的谱系可塑性介质，并为未来的临床策略提供理论基础， 驱动前列腺腺癌向NEPC转变的潜在表观遗传机制。 可塑性，一个分化细胞 他们的身份和获得替代血统计划，最近被确定为一个新兴的 对靶向治疗的耐药性，包括前列腺癌 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