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

项目摘要/摘要 前列腺癌是一种由雄激素引起的疾病，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。尽管最近在发展方面取得了进展 对于高效的AR导向治疗，获得性耐药的发展仍然是一个巨大的挑战。 一个新出现的抗AR抵抗的概念是诱导上皮可塑性进入异质状态，即 已经失去了依赖AR的管腔特征，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(平均存活率=7 月)。NEPC保留了前列腺癌去势过程中出现的许多基因组变化 耐药前列腺癌提示为克隆性起源。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向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的丢失。我们已经证明了N-Myc已经结束了- 在大多数(&gt；95%)的NEPC病例和20%的CRPC肿瘤中表达，这些肿瘤也表现出 NEPC。Rb1缺失发生在大多数NEPC病例(70%)和32%的CRPC肿瘤中，这些肿瘤部分重叠， N-Myc过表达。目前，MYCN诱导和RB1丢失之间的协同作用，机制 在驱动谱系转换中有或不有RB1缺失的MYCN诱导/PTEN缺失诱导下游 和治疗反应还不是很清楚。我们最重要的假设是特定的分子 前列腺癌细胞的改变(例如MYCN诱导)通过建立一种分子来驱动谱系可塑性 与神经谱系和表观基因组重编程相关的程序，作为抵抗 抗AR治疗和向神经内分泌表型的转变。为了解决这一假设，我们有 制定了以下三个具体目标：我们将使用小鼠和人的体外、体内和体外模型 确定N-Myc和下游介体(如NKX2-1，sox11)在基因表达和表达中的作用 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CRPC-Adeno向NEPC转变的转录复合体蛋白(目标2)；最后， 我们将评估靶向CRPC-Adeno向NEPC转变的临床前疗效(目标3)。我们 预计在转化过程中和表观遗传硬连接之前，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。这个 多学科项目建立在PI和CO-IS之间的长期合作和广泛的基础上 初步数据。在这项研究的结论中，我们将对这些机制有更好的理解 潜在的谱系可塑性与AR导向的治疗耐药相关。 好了！

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. !