Defining Molecular Determinants of Lineage Plasticity as a Mechanism of Treatment Resistance in Prostate Cancer

将谱系可塑性的分子决定因素定义为前列腺癌治疗耐药的机制

• 批准号: 10671545
• 负责人: David S. Rickman
• 金额: $ 41.95万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10671545
• 关键词: Acceleration; Address; Adenocarcinoma; Androgen Antagonists; Androgen Receptor; Androgens; Automobile Driving; Back; Binding; Biological Models; Cancer Patient; Castration; Cell Differentiation process; Cell Reprogramming; Cells; Cessation of life; Chromatin; Clinical; Collaborations; DNA Sequence Alteration; Data; Development; Disease; EZH2 gene; Epigenetic Process; Epithelium; Event; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Genetically Engineered Mouse; Goals; Human; In Vitro; Intervention; MYCN gene; Malignant neoplasm of prostate; Mediating; Mediator; Modeling; Molecular; Mus; Neuroendocrine Prostate Cancer; Organoids; Outcome; PTEN gene; Patient Selection; Patient-Focused Outcomes; Patients; Phenotype; Platinum; Process; Prognosis; Prostate Adenocarcinoma; Prostate Cancer therapy; Proteins; Publishing; RB1 gene; Receptor Signaling; Resistance; Role; SOX11 gene; TP53 gene; Therapeutic; Therapeutic Intervention; Up-Regulation; Xenograft procedure; advanced prostate cancer; androgen sensitive; aurora kinase A; biomarker driven; cancer type; castration resistant prostate cancer; cell transformation; chemotherapy; clinically relevant; cofactor; cohort; effective therapy; enzalutamide; epigenomics; improved; in vivo; inhibitor; insight; loss of function; multidisciplinary; neoplastic cell; neural; neuroendocrine phenotype; new therapeutic target; novel; overexpression; personalized cancer care; pharmacologic; preclinical efficacy; programs; prostate cancer cell; prostate cancer cell line; prostate cancer progression; protein complex; resistance mechanism; standard of care; synergism; targeted treatment; therapy resistant; transcriptome; treatment response; tumor

Project Summary/Abstract Prostate cancer arises as an androgen driven disease and therefore therapies targeting the androgen receptor (AR) have been a major focus of prostate cancer treatment. Despite recent advances in the development of highly effective AR-directed therapies, the development of acquired resistance remains a significant challenge. An emerging concept of anti-AR resistance is the induction of epithelial plasticity to a heterogeneous state that has lost its AR-dependent luminal identity and ultimately develops neuroendocrine prostate cancer (NEPC). There are no effective therapies for patients with NEPC and prognosis is extremely poor (average survival = 7 months). NEPC retains many of the genomic alterations that arise in prostate adenocarcinoma castration resistant prostate adenocarcinoma suggesting a clonal origin. Recently, we and others have identified and validated new therapeutic targets and drivers of cell transformation from CRPC to NEPC (e.g. induction of MYCN (encodes N-Myc) or loss of Retinoblastoma-1 (RB1) and TP53. We have shown that N-Myc is over- expressed in the majority (>95%) of NEPC cases and in 20% of CRPC tumors that also display features of NEPC. RB1 loss occurs in majority of NEPC cases (70%) and in 32% of CRPC tumors which overlaps, in part, with N-Myc over-expression. Currently, the synergy between MYCN induction and RB1 loss, mechanisms downstream of induction of MYCN induction/PTEN loss with or without RB1 loss in driving lineage switching and treatment response are not well understood. Our over-arching hypothesis is that specific molecular alterations (e.g. MYCN induction) in prostate cancer cells drive lineage plasticity by establishing a molecular program associated with the neural lineage and epigenomic reprogramming as a mechanism of resistance to anti-AR therapy and transformation towards a neuroendocrine phenotype. To address this hypothesis we have formulated the following three Specific Aims: We will use murine and human in vitro, in vivo and ex vivo models to establish the role of N-Myc and downstream mediators (e.g. NKX2-1, SOX11,) in gene expression and epigenetic reprogramming driving CRPC-Adeno towards NEPC (Aim 1); we will also define essential N-Myc- transcriptional complex proteins that mediate the transition from CRPC-Adeno towards NEPC (Aim 2); finally, we will evaluate the preclinical efficacy of therapy targeting CRPC-Adeno to NEPC transition (Aim 3). We expect that during the transformation process and before epigenetic hardwiring, tumor cells will retain the capacity to revert to a luminal phenotype as a result of molecular or pharmacological intervention. This project leverages unique model systems to study drivers of lineage switching and treatment response. The multidisciplinary project builds upon a long-standing collaboration between the PI and co-Is and extensive preliminary data. At the conclusion of this study, we will have a better understanding of the mechanisms underlying lineage plasticity associated AR-directed treatment resistance. !

项目概要/摘要 前列腺癌是一种雄激素驱动的疾病，因此针对雄激素受体的治疗 （AR）一直是前列腺癌治疗的主要焦点。尽管最近在开发方面取得了进展 虽然高效的 AR 导向疗法，获得性耐药的发展仍然是一个重大挑战。 抗 AR 耐药的一个新兴概念是诱导上皮可塑性达到异质状态， 失去了 AR 依赖性管腔特性，最终发展为神经内分泌前列腺癌 (NEPC)。 NEPC 患者没有有效的治疗方法，预后极差（平均生存期 = 7 月）。 NEPC 保留了前列腺腺癌去势过程中出现的许多基因组改变 耐药性前列腺癌提示克隆起源。最近，我们和其他人已经确定并 验证了新的治疗靶点和细胞从 CRPC 到 NEPC 转化的驱动因素（例如诱导 MYCN（编码 N-Myc）或视网膜母细胞瘤-1 (RB1) 和 TP53 丢失。我们已经证明 N-Myc 过度- 在大多数 (>95%) NEPC 病例和 20% CRPC 肿瘤中表达，这些肿瘤也表现出 国家电力委员会。 RB1 缺失发生在大多数 NEPC 病例 (70%) 和 32% 的 CRPC 肿瘤中，两者部分重叠， N-Myc 过度表达。目前，MYCN诱导与RB1丢失之间的协同作用、机制 MYCN 诱导/PTEN 损失诱导下游，有或没有 RB1 损失驱动谱系转换 和治疗反应尚不清楚。我们的首要假设是特定的分子 前列腺癌细胞中的改变（例如 MYCN 诱导）通过建立分子机制来驱动谱系可塑性 与神经谱系和表观基因组重编程相关的程序作为抵抗机制 抗 AR 治疗和向神经内分泌表型的转化。为了解决这个假设，我们有 制定了以下三个具体目标：我们将使用小鼠和人类的体外、体内和离体模型 确定 N-Myc 和下游介质（例如 NKX2-1、SOX11）在基因表达和 表观遗传重编程驱动 CRPC-Adeno 走向 NEPC（目标 1）；我们还将定义必需的 N-Myc- 介导从 CRPC-Adeno 向 NEPC 转变的转录复合蛋白（目标 2）；最后， 我们将评估针对 CRPC-Adeno 向 NEPC 过渡的治疗的临床前疗效（目标 3）。我们 预计在转化过程中和表观遗传硬连线之前，肿瘤细胞将保留 由于分子或药物干预而恢复管腔表型的能力。这个项目 利用独特的模型系统来研究谱系转换和治疗反应的驱动因素。这 多学科项目建立在 PI 和 co-Is 之间的长期合作以及广泛的 初步数据。在本研究结束时，我们将对机制有更好的了解 潜在的谱系可塑性与 AR 导向的治疗耐药性相关。 ！