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

“DNMT 和 TET1 重编程作为晚期前列腺癌的靶向耐药机制”

基本信息

批准号：
10681632
负责人：
Himisha Beltran
金额：
$ 66.29万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10681632
关键词：
ASCL1 gene Address Adenocarcinoma Androgen Antagonists Androgen Receptor Androgens Antiandrogen Therapy Automobile Driving CRISPR/Cas technology Cancer Patient Castration Cell Differentiation process Cell Survival Chromatin Clinical DNA Methylation DNA Modification Methylases DNA Sequence Alteration DNMT3B gene Data Development Disease Epigenetic Process Epithelium Future Gene Expression Genetic Models Genetically Engineered Mouse Genome Goals Histologic In Vitro Intervention Knock-out MYCN gene Maintenance Malignant Neoplasms Malignant neoplasm of prostate Mediator Methylation Modeling Molecular Neoplasm Metastasis Neuroendocrine Prostate Cancer Neurosecretory Systems Organ Organoids Patient Selection Patients Phenotype Process Prognosis Prostate Prostate Adenocarcinoma Prostate Cancer therapy Protein Methylation Publishing RB1 gene Reader Receptor Inhibition Receptor Signaling Regulation Resistance Role Site Small Cell Carcinoma Specificity Therapeutic Time Visceral Withdrawal Xenograft procedure advanced prostate cancer androgen sensitive antagonist biomarker driven cancer type castration resistant prostate cancer clinically relevant deprivation effective therapy enzalutamide epigenome epigenomics in vivo insight multidisciplinary mutant neoplastic cell novel personalized cancer care pharmacologic prevent programs prostate cancer cell prostate cancer progression resistance mechanism synergism targeted agent targeted treatment transcription factor transcriptome tumor

项目摘要

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

项目摘要/摘要前列腺癌作为一种雄激素驱动疾病，因此靶向疗法的雄激素受体（AR）一直是前列腺癌治疗的主要重点。血统失去机制癌症组织学转化从AR阳性前列腺腺癌到一种表达神经内分泌标记物的Ar阴性小细胞癌，通常称为神经内分泌前列腺癌（NEPC）。 NEPC在临床上是侵略性的，预后很差。所以， NEPC患者的有效治疗仍然是未满足的临床需求。对为这种致命疾病开发有效治疗需要NEPC进展。虽然NEPC 肿瘤是由前列腺腺癌的克隆出现的，并具有共同的基因组改变，存在明显的在转化过程中的表观遗传放松管制。但是，从机械上讲，我们仍然不知道如何这些表观遗传改变以及如何最好地利用这些改变作为治疗机会。我们的来自体内的初步和发表的数据，体外和离体模型（NEPC-Patient衍生的类器官）表明N-MYC转录组和Cistrome是雄激素依赖性的，并驱动上皮可塑性和获得与临床相关的NEPC分子程序的获取和表观基因组的重编程。最多最近，根据来自新的一般工程鼠标模型（GEM）的数据，我们发现N-MYC诱导与RB1损失协同作用，以放大管制DNA甲基化读取器，作家（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了特定的分子或药物干预措施可以将NEPC表型恢复到腔内 - 更易于临床管理 - 腺癌表型。我们基于我们已发表和初步数据的规范假设是特定的前列腺癌细胞中的分子改变（例如MYCN诱导/RB1损失）驱动谱系可塑性通过表观遗传重编程（即DNA甲基化）作为对抗AR治疗的抗药性的机制导致转化为NEPC。为了解决这一假设，我们将采用患者衍生的类器官和元素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与NEPC相关的DNA甲基化程序（AIM 1）时，表征了上游调节 DNMTS在向NEPC的进展中表达（AIM 2）并评估DNMT的治疗潜力单独抑制或与AR靶向疗法结合使用以阻止向或维持NEPC的过渡或维持（目标3）。这些目标的成功完成将为NEPC开发提供独特的见解，确定关键以及谱系可塑性的潜在目标介体，并为未来的临床策略提供基本原理驱动从前列腺腺癌到NEPC的过渡的基本表观遗传机制。可塑性，一个分化细胞的过程他们的身份并获得替代血统计划，最近被确定为新兴在包括前列腺癌的几种癌症类型中对靶向疗法的抗性这种可塑性可以表现为。为了