"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

项目概要/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。失去机制从 AR 阳性前列腺癌到癌症组织学转变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）在临床上具有侵袭性，因此预后较差。对 NEPC 患者的有效治疗仍然是一个未满足的临床需求。虽然 NEPC 是一种致命疾病，但开发有效的治疗方法仍需要 NEPC 的进展。肿瘤由前列腺腺癌克隆产生并具有基因组改变，因此存在显着的差异然而，从机械角度来看，我们仍然不知道转化过程中的表观遗传放松管制是如何发生的。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我们的治疗机会。来自体内、体外和离体模型（NEPC-患者来源的类器官）的初步和已发表的数据表明 N-Myc 转录组和顺反组是雄激素依赖性的并驱动上皮可塑性和获得临床相关的 NEPC 分子程序和表观基因组的重编程。最近，基于新的基因工程小鼠模型（GEM）的数据，我们发现 N-Myc 诱导与 RB1 损失协同作用，解除 DNA 甲基化读取器、写入器（例如 DNMT1 和 DNMT3B）的管制隐含地，我们和其他人已经证明了特定的分子或药理学。干预措施可以将 NEPC 表型恢复为临床上更易于管理的管腔腺癌我们的总体假设是基于我们已发表的初步数据。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 治疗的抵抗机制为了解决这一假设，我们将采用源自患者的类器官并异种移植和新型基因工程小鼠模型阐明 DNMT/TET1 的作用和特异性建立 NEPC 相关 DNA 甲基化程序（目标 1），表征 DNMT 在 NEPC 进展中的表达（目标 2）并评估 DNMT 的治疗潜力单独抑制或与 AR 靶向治疗组合以阻止 NEPC 的转变或维持（目标 3）成功完成这些目标将为 NEPC 的发展提供独特的见解，确定关键点。和谱系可塑性的潜在可靶向介质，并为未来的临床策略提供理论基础驱动从前列腺腺癌向 NEPC 转变的潜在表观遗传机制。可塑性，分化细胞的过程他们的身份并获得替代血统计划，最近被确定为一种新兴的包括前列腺癌在内的多种癌症类型对靶向治疗的耐药性这种可塑性可以表现为。为了