Targeting Genomic Instability in Lethal Neuroendocrine Prostate Cancer

针对致命性神经内分泌前列腺癌的基因组不稳定性

• 批准号: 10405055
• 负责人: THOMAS G GRAEBER
• 金额: $ 51.96万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-06 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405055
• 关键词: AKT1 gene; Adenocarcinoma; Androgens; Aneuploid Cells; Aneuploidy; Automobile Driving; BCL2 gene; BRCA2 gene; Bioinformatics; Biological Models; Biology; Cancer Biology; Cancer Histology; Cancer Model; Cancerous; Candidate Disease Gene; Cells; Chromosomal Instability; Clinical; Cohort Studies; DNA Repair; DNA copy number; Diploidy; Epithelial Cells; Equilibrium; Event; Evolution; Experimental Models; Gene Dosage; Gene Mutation; Genes; Genetic; Genome; Genomic Instability; Genomics; Growth; Histology; Human; Individual; KRAS2 gene; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mitosis; Modeling; Molecular Classification of Tumors; Monitor; Movement; Mutation; Neuroendocrine Carcinoma; Neuroendocrine Prostate Cancer; Neurosecretory Systems; Oncogenes; Organ; Organoids; Outcome; Patients; Pattern; Penetrance; Phenotype; Preclinical Testing; Prognosis; Prostate; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Public Health; Quality of life; RB1 gene; Recurrence; Resistance; Resolution; Role; Route; Sampling; Signal Transduction; Stress; Sum; System; Systems Biology; TP53 gene; Testing; The Cancer Genome Atlas; Therapeutic; Tissues; Tumor Suppressor Genes; abiraterone; advanced prostate cancer; aggressive therapy; base; cancer cell; cancer genome; cancer subtypes; castration resistant prostate cancer; cell transformation; clinically relevant; enzalutamide; genetic manipulation; human disease; improved; in vivo Model; mutant; new technology; pressure; programs; prostate cancer cell; repaired; targeted treatment; therapeutic target; therapy resistant; transdifferentiation; tumor; tumorigenesis

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.

项目摘要 对于高度侵略性和致命的患者，鉴定治疗靶标有至关重要的临床需求 前列腺癌。虽然染色体不稳定长期以来一直被认为是高级前列腺的标志 癌症，我们对影响破坏癌症基因组的机制（非整倍性和DNA拷贝 数量变化）及其如何对侵略性表型的贡献受到限制。最近的大型队列研究 已经揭示了前列腺和其他癌症中高度复发的DNA拷贝数改变（CNA） - 但是 这种保守的癌症基因组演变背后的截面力尚未完全了解。在前列腺中 癌症，有广泛的结果和基因组不稳定性相关的非整倍性。器官限制， 更好的前列腺癌预后病例通常是二倍体。虽然抗治疗，但结局案件不佳 高度肾上腺素。改善了靶向雄激素的前列腺疗法（例如恩扎拉胺和阿比罗酮） 生活质量，但肿瘤经常通过涉及转差的机制逃脱治疗 nuereencrine前列腺癌（NEPC）亚型。 NEPC是高度侵略性的，因此至关重要 更好地了解该亚型的生物学和治疗脆弱性。 DNA拷贝数改变对驾驶侵略性癌症表型的贡献不足 理解。在这里，我们提出了一项系统的研究，以使用集成的OMIC来识别基因和突变 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其作用。 我们的项目集中在以下假设的基础上，总的来说，激活癌基因突变，肿瘤抑制基因 损失，更微妙但丙烯酸坐标的CNA模式变化各自有助于积极进取 癌症表型。我们将使用前列腺转换模型通过改变平衡来检验这一假设 在强大的致癌基因贡献和基于CNA的贡献之间，基因组不稳定性使 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，我们将开发更类似于人类疾病的模型系统。因此，我们将使用我们的 模型是确定基因促进或启用基因组不稳定性的临床前测试场 可以热靶向的阿喀琉斯高跟鞋。 我们的项目是扩大肿瘤分子分类的新运动的一部分 基因组不稳定性的基本机制，并了解如何链接受限的完善 基因组可以有助于侵袭性肿瘤表型。肿瘤演化如何优化的复杂性 链接受限的拷贝数更改是系统生物学方法的强大拟合度。我们的项目将利用 Witte Lab的癌症生物学和建模专业知识，具有癌症系统的生物学专业知识 Graeber实验室。