Targeting Genomic Instability in Lethal Neuroendocrine Prostate Cancer

项目摘要 有一个关键的临床需要，以确定治疗目标的患者具有高度侵略性和致命性， 前列腺癌虽然染色体不稳定性长期以来被认为是晚期前列腺疾病的标志物， 癌症，我们对诱导癌症基因组破坏的机制（非整倍体和DNA拷贝）的理解 数量改变）以及它们如何促成攻击性表型是有限的。近期大型队列研究 已经揭示了前列腺癌和其他癌症中高度复发的DNA拷贝数改变（CNA）-但 在癌症基因组的这种保守进化背后的部分力量还没有被完全理解。前列 在癌症中，存在广泛的结果和与非整倍体相关的基因组不稳定性。器官受限， 预后较好的前列腺癌病例通常是二倍体;而耐药的预后较差的病例是二倍体。 高度非整倍体。改进的雄激素靶向前列腺治疗（如Enzalutamide和阿比特龙）影响 生活质量，但肿瘤往往逃避治疗的机制，涉及转分化， 神经内分泌前列腺癌（NEPC）亚型。NEPC具有高度侵略性，因此迫切需要 更好地了解这种亚型的生物学和治疗弱点。 DNA拷贝数改变对驱动侵袭性癌症表型的贡献是不够的， 明白在这里，我们提出了一个系统的研究，使用整合组学来确定基因和突变 与染色体不稳定性相关，并在NEPC前列腺癌的实验模型中测试它们的作用。 我们的项目是集中在这样的假设，即总的来说，激活癌基因突变，肿瘤抑制基因， 损失，以及CNA模式中更微妙但累积的坐标变化都有助于攻击性 癌症表型我们将使用我们的前列腺转化模型，通过改变平衡来验证这一假设。 强致癌基因贡献和基于CNA的贡献之间的差异，这是由基因组不稳定性实现的， 测试所得肿瘤的侵袭性表型。我们预计，通过增加基因组的作用， 不稳定性，我们将开发更接近人类疾病的模型系统。因此，我们将使用我们的 模型作为临床前试验场，用于确定促进或使基因组不稳定性的基因是否 阿基里斯之踵可以作为治疗目标。 我们的项目是一个新的运动的一部分，扩大肿瘤的分子分类，包括肿瘤的分子分类。 基因组不稳定性的潜在机制，并了解如何链接约束的细化， 基因组可以导致侵袭性肿瘤表型。肿瘤进化的复杂性 连接约束的拷贝数变化是系统生物学方法的稳健拟合。我们的项目将利用 Witte实验室的癌症生物学和建模专业知识， 格雷伯实验室。

PROJECT SUMMARY There is a crucial clinical need to identify therapeutic targets for patients with highly aggressive and lethal prostate cancer. While chromosome instability has long been recognized as a marker of advanced prostate cancer, our understanding of the mechanisms that induce disrupted cancer genomes (aneuploidy and DNA copy number alterations) and how they contribute to aggressive phenotypes is limited. Recent large cohort studies have revealed highly recurrent DNA copy number alterations (CNA) in prostate and other cancers – but the section forces behind this conserved evolution of the cancer genome are not completely understood. In prostate cancer, there is a wide spectrum of outcomes and of genomic instability associated aneuploidy. Organ confined, better prognosis cases of prostate cancer are typically diploid; while therapy-resistant, poor outcome cases are highly aneuploid. Improved androgen-targeted prostate therapies (e.g. enzalutamide and abiraterone) impact quality of life, but tumors frequently escape therapy through mechanisms involving transdifferentiation to the nueroendocrine prostate cancer (NEPC) subtype. NEPC is highly aggressive, and thus there is a vital need to better understand the biology and therapeutic vulnerabilities of this subtype. The contribution of DNA copy number alterations to driving aggressive cancer phenotypes is insufficiently understood. Here we propose a systematic study to use integrated omics to identify genes and mutations associated with chromosome instability and test their roles in an experimental model of NEPC prostate cancer. Our project is centered on the hypothesis that in sum, activating oncogene mutations, tumor suppressor gene loss, and more subtle but accumulative coordinate changes in CNA patterns are each contributing to aggressive cancer phenotypes. We will use our prostate transformation model to test this hypothesis by altering the balance between strong oncogene contributions and CNA-based contributions, enabled by genomic instability, and testing the aggressive phenotypes of the resulting tumors. We anticipate that by increasing the role of genomic instability, we will develop model systems that more closely resemble the human disease. We will thus use our model as a pre-clinical testing ground for determining if the genes promoting or enabling genomic instability are Achilles’ heels that can be therapeutically targeted. Our project is part of a newer movement to expand the molecular classification of tumors to include the underlying mechanisms of genomic instability, and to understand how linkage-constrained refinement of the genome can contribute to aggressive tumor phenotypes. The complexity of how tumor evolution optimizes linkage-constrained copy number changes is a robust fit to a systems biology approach. Our project will leverage the cancer biology and modeling expertise of the Witte lab with the cancer systems biology expertise of the Graeber lab.