Targeting Genomic Instability in Lethal Neuroendocrine Prostate Cancer

项目总结 临床上迫切需要确定高度侵袭性和致命性疾病的治疗靶点。 前列腺癌。虽然染色体不稳定长期以来被认为是晚期前列腺癌的标志 癌症，我们对导致癌症基因组中断的机制(非整倍体和DNA复制)的理解 数量改变)，以及它们对攻击性表型的贡献是有限的。最近的大型队列研究 在前列腺癌和其他癌症中发现了高度复发的DNA拷贝数改变(CNA)--但 癌症基因组这种保守进化背后的区段作用力还没有完全被理解。在前列腺中 对于癌症，有广泛的结局和与非整倍体相关的基因组不稳定性。器官受限， 前列腺癌预后较好的病例通常是二倍体；而耐药、预后差的病例则是 高度非整倍体。改进的雄激素靶向前列腺治疗(如苯扎鲁胺和阿比特龙)影响 生活质量，但肿瘤经常通过转分化机制逃脱治疗 神经内分泌前列腺癌(NEPC)亚型。NEPC具有很强的攻击性，因此迫切需要 更好地了解这一亚型的生物学和治疗脆弱性。 DNA拷贝数改变对推动侵袭性癌症表型的作用是不够的 明白了。在这里，我们提出了一项系统的研究，使用集成组学来识别基因和突变 并在NEPC前列腺癌的实验模型中测试它们的作用。 我们的项目的中心假设是，总的来说，激活癌基因突变，肿瘤抑制基因 损失，以及CNA模式中更细微但累积的坐标变化，每个都有助于攻击性 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检验这一假设。 在强大的癌基因贡献和基于CNA的贡献之间，由基因组不稳定实现，以及 测试由此产生的肿瘤的侵袭性表型。我们预计，通过增加基因组的作用 在不稳定的情况下，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来确定促进或使基因组不稳定的基因是否 阿喀琉斯的高跟鞋可以作为治疗靶点。 我们的项目是一项新运动的一部分，该运动旨在将肿瘤的分子分类扩大到包括 基因组不稳定的潜在机制，并理解连锁约束的精化是如何 基因组可以促进侵袭性肿瘤的表型。肿瘤进化如何优化的复杂性 连锁约束的拷贝数变化是一种适合系统生物学方法的健壮方法。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与 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.