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

项目总结/摘要 前列腺癌是一种雄激素驱动的疾病，因此靶向雄激素受体的治疗 (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， 尽管使用高效的AR导向疗法，但获得性耐药性的发展仍然是一个重大挑战。 抗AR抗性的一个新兴概念是诱导上皮可塑性至异质状态， 已经失去其AR依赖性管腔特性，并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中出现的许多基因组改变 耐药前列腺腺癌提示克隆起源。最近，我们和其他人已经确定， 经验证的新的治疗靶点和从CRPC向NEPC转化的细胞驱动因素（例如诱导 MYCN（编码N-Myc）或视网膜母细胞瘤-1（RB 1）和TP 53缺失。我们已经证明了N-Myc是过度的- 在大多数（>95%）NEPC病例和20%的CRPC肿瘤中表达， NEPC。RB 1缺失发生在大多数NEPC病例（70%）和32%的CRPC肿瘤中， N-Myc过度表达。目前，MYCN诱导和RB 1损失之间的协同作用， MYCN诱导/PTEN缺失的诱导下游，伴或不伴RB 1缺失，驱动谱系转换 和治疗反应还不清楚。我们的过度假设是， 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对 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：我们将使用鼠和人在体外，体内和离体模型 确定N-Myc和下游介质（例如NKX 2 -1、SOX 11）在基因表达中的作用， 表观遗传重编程驱动CRPC-Adeno向NEPC（目标1）;我们还将定义必需的N-Myc- 介导从CRPC-Adeno向NEPC转变的转录复合物蛋白（Aim 2）;最后， 我们将评估靶向CRPC-Adeno向NEPC转化的治疗的临床前疗效（目的3）。我们 预期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到管腔表型的能力。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。的 多学科项目建立在PI和co-Is之间的长期合作基础上， 初步数据。在本研究结束时，我们将有一个更好的了解机制， 潜在的谱系可塑性相关的AR导向的治疗抗性。 !

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. !