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

• 批准号: 9763528
• 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
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9763528
• 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

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.

概要：项目4 基因组不稳定性是人类癌症的基本特征。某些癌症类型隐藏着潜在的缺陷 因此对引入DNA损伤的治疗策略特别敏感（例如， BRCA 1突变乳腺癌和卵巢癌）。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。 然而，遗传改变PCa易感染色体重排仍然在很大程度上不确定。 全基因组测序表明，PCa携带复发性SPOP点突变（SPOPmut）， 与其他临床定位的前列腺癌相比，显示出显著更高数量的基因组重排。 这些观察结果提出了SPOP突变，PCa肿瘤发生的早期事件，导致PCa肿瘤发生的可能性。 基因组的不稳定性。 初步研究表明，大约10%的PCa是SPOPmut，这些代表了一种独特的 分子亚类体外初步研究表明，表达SPOP突变的细胞 由于DNA修复过程的改变而积累DNA双链断裂（DSB）。与此孢子相关 我们的研究表明，SPOP突变导致对DNA损伤治疗药物的敏感性增加， 药物如电离辐射和聚（ADP-核糖）聚合酶（PARP）抑制剂。基于这些 观察，我们假设SPOP突变促进基因组重排的积累 通过受损的DSB修复，PCa的SPOPmut亚类可能选择性地对DNA- 破坏性疗法，提名替代治疗策略。我们将使用一个 研究内源性SPOP突变的新型体外平台（类器官），体内小鼠模型测试 SPOP突变对DNA损伤反应的影响，以及患者样本以确定SPOPmut的反应 DNA损伤疗法的患者。 这个高度合作的项目汇集了PCF和SU 2C支持的既定调查人员- PCF现在将研究SPOPmut PCa的翻译方面。使用类器官，最先进的老鼠 模型和尖端的患者分析，我们将影响如何使用DNA损伤剂的临床试验， 合理设计和分析。