Project 4: Targeting Genomic Instability in Distinct Subclasses of Prostate Cancer

项目 4：针对前列腺癌不同亚类的基因组不稳定性

基本信息

批准号：
10227733
负责人：
Christopher E Barbieri
金额：
$ 34.39万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-30 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10227733
关键词：
Address Adjuvant Adjuvant Radiotherapy Affect Automobile Driving BRCA1 gene Biological Markers Cells Characteristics Chromosomal Rearrangement Clinical Clinical Trials DNA Damage DNA Double Strand Break DNA Repair DNA Sequence Alteration DNA Sequence Rearrangement Data Defect Development Disease Disease Progression Double Strand Break Repair Event Foundations Future Genes Genetically Engineered Mouse Genomic Instability Genomics Human Impairment In Vitro Ionizing radiation Lead Lesion Localized Disease Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of prostate Medicine Modeling Molecular Mutation Organoids Outcome PTEN gene Pathogenesis Patients Pattern Point Mutation Poly(ADP-ribose) Polymerases Polymerase Process Prostate Prostate Cancer therapy Publishing Radiation therapy Radical Prostatectomy Recurrence Reporter Research Personnel Role Sampling TMPRSS2 gene Testing Therapeutic Therapeutic Agents Therapeutic Trials Transgenic Organisms Work advanced disease alternative treatment base bench to bedside biomarker-driven cancer genome cancer initiation cancer type cohort design genome sequencing homologous recombination in vivo inhibitor/antagonist malignant breast neoplasm men mouse model mutant mutational status novel patient response pre-clinical prostate cancer cell line prostate carcinogenesis repaired response standard of care structural genomics treatment strategy tumor tumorigenesis ubiquitin-protein ligase whole genome

项目摘要

SUMMARY: PROJECT 4 Genomic instability is a fundamental feature of human cancer. Certain cancer types harbor underlying defects in DNA repair and thus are particularly susceptible to therapeutic strategies introducing DNA damage (e.g., BRCA1 mutant breast and ovarian cancers). In prostate cancer (PCa), structural genomic rearrangements, including translocations and copy number aberrations, are a common mechanism driving tumorigenesis. However, genetic alterations in PCa predisposing to chromosomal rearrangements remain largely undefined. Whole genome sequencing demonstrates that PCa harboring recurrent point mutations in SPOP (SPOPmut) display significantly higher numbers of genomic rearrangements compared with other clinically localized PCas. These observations raise the possibility that SPOP mutations, early events in PCa tumorigenesis, lead to genomic instability. Preliminary studies demonstrate that around 10% of PCa are SPOPmut, and these represent a distinct molecular subclass. Preliminary studies in vitro demonstrate that cells expressing SPOP mutations accumulate DNA double-strand breaks (DSBs) due to altered DNA repair processes. Relevant to this SPORE project, we have shown that SPOP mutation results in increased sensitivity to DNA-damaging therapeutic agents such as ionizing radiation and poly (ADP-ribose) polymerase (PARP) inhibitors. Based on these observations, we hypothesize that SPOP mutation promotes accumulation of genomic rearrangements through impaired DSB repair and the SPOPmut subclass of PCa may be selectively responsive to DNA- damaging therapeutics, nominating alternative treatment strategies. We will test this hypothesis using a novel in vitro platform (organoids) to study endogenous SPOP mutations, in vivo mouse models testing the effect SPOP mutation on DNA damage response, and patient samples to define the response of SPOPmut patients to DNA damaging therapies. This highly collaborative project brings together established investigators supported by the PCF and SU2C- PCF who will now study the translational aspects of SPOPmut PCa. Using organoids, state-of-the-art mouse models, and cutting edge patient analyses, we will impact how clinical trials using DNA-damaging agents are rationally designed and analyzed.

摘要：项目4 基因组不稳定性是人类癌症的基本特征。某些癌症类型具有潜在缺陷在DNA修复中，因此特别容易受到引入DNA损伤的治疗策略（例如， BRCA1突变乳腺和卵巢癌）。在前列腺癌（PCA）中，结构基因组重排，包括易位和拷贝数畸变，是驱动肿瘤发生的常见机制。但是，PCA的遗传改变易于染色体重排，在很大程度上不确定。整个基因组测序表明，PCA含有斑点中的复发点突变（Spopmut）与其他临床定位的PCA相比，基因组重排的数量明显更高。这些观察结果提出了一种可能性，即SPOP突变，PCA肿瘤发生的早期事件引导基因组不稳定性。初步研究表明，大约10％的PCA是Spopmut，这些是一个独特的分子亚类。体外的初步研究表明，表达Spop突变的细胞由于DNA修复过程的改变，累积的DNA双链断裂（DSB）。与此孢子有关项目，我们已经表明，SPOP突变会增加对DNA伤害治疗的敏感性电离辐射和聚（ADP-核糖）聚合酶（PARP）抑制剂等药物。基于这些观察结果，我们假设SPOP突变促进了基因组重排的积累通过受损的DSB修复和PCA的SpopMut子类可有选择地响应DNA- 破坏治疗学，提名替代治疗策略。我们将使用新型体外平台（类器官）研究内源性蜘蛛突变，体内小鼠模型测试对DNA损伤反应的影响SPOP突变和患者样品定义SpopMut的响应患者进行DNA破坏疗法。这个高度协作的项目将PCF和SU2C-支持的既定研究人员汇集在一起 PCF现在将研究Spopmut PCA的翻译方面。使用类器官，最先进的鼠标模型和尖端的患者分析，我们将影响使用DNA损害剂的临床试验的方式理性设计和分析。