Preclinical analyses of advanced prostate cancer in genetically-engineered mice

项目摘要/摘要 大多数前列腺癌的死亡是由于治疗反应失败或转移，特别是骨骼转移。 我们一直在用基因工程小鼠研究治疗失败的机制。 概括晚期前列腺癌关键特征的模型(GEM)，包括抗去势 前列腺癌(CRPC)和侵袭性变异型CRPC伴神经内分泌分化(CRPC-NE) 发展为高穿透性转移性前列腺癌，包括转移到骨，这是 人类。使用新的跨物种计算方法，我们已经证明了潜在的机制 这些GEMM的疾病进展与人类前列腺癌是保守的，而药物反应在 GEMM可以预测人类的药物反应。在我们的主要发现中，我们已经表明，GEMM 基于在人类CRPC中经常共突变的Pten和P53(NPP53)的联合功能丧失， 治疗诱导的侵袭性变异CRPC的关键表型和分子特征模型。不仅是这些 NPP53小鼠对抗雄激素治疗无效，治疗实际上加速了疾病的发展， 我们称之为特殊的无响应者。此外，我们还表明，治疗诱导的 这些特殊无反应者的神经内分泌表型(CRPC-NE)与谱系可塑性有关。 因此，我们建议的研究将检验以下假设：(I)对GEMM和人类的共同临床分析 前列腺癌可以阐明药物反应的生物学和分子机制，以及(Ii)谱系可塑性 是一种重要的新型耐药机制。在目标1中，我们将进行联合临床研究。 利用我们的GEMM，模拟晚期前列腺癌的关键方面，并补充 人前列腺癌器官模型的分析。我们将评估临床相关药物的疗效。 以及药物组合，重点是：(A)抵消与治疗相关的细胞可塑性 耐药的CRPC；和(B)靶向骨转移。在目标2中，我们将研究药物的分子机制。 利用我们的全基因组监管网络进行响应，实现数据之间的跨物种整合 来自GEMM和人类前列腺癌。我们将重点找出“治疗反应监管机构”， 告知对以下情况的反应：(I)谱系可塑性和/或(Ii)骨转移。在目标3中，我们将确定 使用正向基因筛查方法的晚期前列腺癌。为此，我们进行了一项 利用睡美人(SB)小鼠转座子系统进行遗传筛选，结果表明，小鼠 携带激活的转座子显示加速了致命性前列腺癌的表型。总而言之， 这些目标的成功实现将确定对药物治疗和 药物反应的分子机制，并将确定新的干预靶点。

Project Summary/Abstract Most prostate cancer deaths are due to failed treatment response or to metastasis, particularly to bone. We have been studying the mechanisms responsible for treatment failure using genetically-engineered mouse models (GEMMs) that recapitulate key features of advanced prostate cancer, including castration-resistant prostate cancer (CRPC) and aggressive-variant CRPC with neuroendocrine differentiation (CRPC-NE), and that develop highly penetrant metastatic prostate cancer including to bone, which is the primary site of metastasis in humans. Using novel cross-species computational approaches, we have shown that the mechanisms underlying disease progression in these GEMMs are conserved with human prostate cancer, while drug response in GEMMs can be predictive of drug response in humans. Among our major findings, we have shown that GEMMs based on combined loss-of-function of Pten and p53 (NPp53), which are frequently co-mutated in human CRPC, model key phenotypic and molecular features of treatment-induced aggressive variant CRPC. Not only do these NPp53 mice fail to respond to treatment with anti-androgens, treatment actually accelerates disease progression, which we have called exceptional non-responders. Furthermore, we have shown that the treatment-induced neuroendocrine phenotype (CRPC-NE) of these exceptional non-responders is related to lineage plasticity. Thus, our proposed studies will test the hypotheses that: (i) co-clinical analyses of GEMMs and human prostate cancer can elucidate biological and molecular mechanisms of drug response, and (ii) lineage plasticity is an important novel mechanism of drug resistance. In Aim 1 we will perform co-clinical investigations capitalizing on our GEMMs that model key aspects of advanced prostate cancer, and complemented with analyses of human prostate cancer organoid models. We will evaluate the efficacy of clinically-relevant drugs and drug combinations, focusing on those that: (a) counteract cellular plasticity associated with treatment resistance in CRPC; and (b) target bone metastasis. In Aim 2, we will investigate molecular mechanisms of drug response leveraging our genome-wide regulatory networks that enable cross-species integration between data from GEMMs and human prostate cancer. We will focus on identifying “treatment response regulators” that inform on response to: (i) lineage plasticity and/or (ii) bone metastasis. In Aim 3 we will identify novel drivers of advanced prostate cancer using a forward genetic screening approach. Toward this end, we have undertaken a genetic screen utilizing the Sleeping Beauty (SB) murine transposon-based system, and have shown that mice harboring the activated transposon display accelerated lethal prostate cancer phenotypes. Taken together, the successful implementation of these Aims will identify tumor contexts that are responsive to drug treatment and molecular mechanisms of drug response, and will identify new targets for intervention.