RNASEH2B loss to predict response to PARP inhibitor in prostate cancer

RNASEH2B 缺失可预测前列腺癌对 PARP 抑制剂的反应

基本信息

批准号：
10199307
负责人：
Li Jia
金额：
$ 25.1万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-10 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10199307
关键词：
13q14 Affect Androgen Antagonists Androgen Receptor BRCA mutations BRCA1 gene BRCA2 gene Biological Assay CRISPR screen CRISPR/Cas technology Cancer Patient Cell Death Cell Lineage Cell model Cessation of life Chromatin Chromosomes Clinical Clinical Trials DNA Damage DNA Repair DNA Sequence Alteration DNA biosynthesis Data Set Defect Disease Disease remission Enzymes Event Excision Repair Future Generations Genes Genetic Genetic Engineering Genomics Goals Human Hypersensitivity In Vitro Knock-out Knockout Mice Lead Lesion Life Malignant neoplasm of prostate Measures Mediating Molecular Target Mouse Cell Line Mutate Mutation Patients Play Poly(ADP-ribose) Polymerases Proteins RB1 gene Research Resistance Ribonucleases Ribonucleotides Role TP53 gene Testing The Cancer Genome Atlas Therapeutic United States Work abiraterone advanced prostate cancer androgen deprivation therapy base brca gene cancer cell castration resistant prostate cancer effective therapy gene discovery genome-wide homologous recombination improved in vivo inhibitor/antagonist men mouse model neoplastic cell new therapeutic target novel personalized medicine potential biomarker pre-clinical predicting response prevent prostate cancer cell prostate cancer cell line prostate cancer model recombinational repair resistance mechanism response targeted treatment tumor

项目摘要

ABSTRACT Metastatic castration-resistant prostate cancer (CRPC) is an incurable disease that is expected to account for ~ 31,000 deaths each year in the United States. There are limited therapeutic options for metastatic CRPC patients that extend life. There is an urgent need for developing novel targeted therapies, especially personalized therapies based on genomic alterations in tumors. Recent genomic studies have revealed a variety of actionable molecular targets with underlying genomic alterations. Notably, alterations in genes involved in DNA damage response (DDR) are among the most common genetic events and enriched in metastatic CRPC. These alterations have been correlated with particular therapeutic vulnerabilities in prostate cancer (PCa) cells. Specifically, defects in homologous recombination (HR) repair would predict sensitivity to inhibition of Poly (ADP-ribose) polymerase (PARP). PARP inhibitors (PARPi) are a new type of targeted therapy, which works by preventing the enzyme PARP from repairing damaged DNA in tumor cells. BRCA1/2 encode proteins essential for HR repair. Cancer cells lacking BRCA1/2 depend instead on PARP-regulated DNA repair and are hypersensitive to PARPi. The U.S. FDA has approved two PARP inhibitors (olaparib and rucaparib) for treatment of metastatic CRPC patients with HR repair mutations (or deleterious BRCA mutations) based on the results from recent clinical trials. One of the major barriers to effective treatment using PARPi is how to select patients who most likely benefit from PARP inhibition. BRCA mutations can predict PARPi response with 50-60% accuracy. However, the degree to which patients with non-BCRA genomic alterations respond to PARPi remains unclear. Through a genome-wide CRISPR screen, we have recently discovered that loss of RNASEH2B in PCa cells may predict response to PARP inhibition. RNASEH2B is one of the three RNase H2 subunits that are thought to play a role in DNA replication. A recent study has demonstrated its function in ribonucleotide excision repair, which may contribute to PARP-trapping lesions. Importantly, analysis of TCGA datasets revealed RNASEH2B deep deletions in 17% of PCa tumors. Co-deletion of RNASEH2B and RB1 on chromosome13q14 frequently occurs. In addition, the results from our CRISPR screening further suggest that loss of TP53 may render PCa cells resistance to PARPi. Therefore, the goal of this project is to determine (1) to what extent loss of RNASEH2B confers a cellular response to PARPi in preclinical PCa models; (2) to what extent inactivation of TP53 and RB1 influences the response to PARPi. The successful implementation of this project will set the stage for future clinical trials in PCa patients with RNASEH2B/TP53/RB1 alterations and significantly expand the pool of eligible patients for PARP inhibition.

抽象的转移性去势抵抗性前列腺癌（CRPC）是一种无法治愈的疾病，预计将导致美国每年约有 31,000 人死亡。转移性 CRPC 的治疗选择有限延长生命的患者。迫切需要开发新型靶向疗法，特别是基于肿瘤基因组改变的个性化治疗。最近的基因组研究揭示了具有潜在基因组改变的各种可操作的分子靶标。值得注意的是，基因的改变参与 DNA 损伤反应 (DDR) 是最常见的遗传事件之一，并且富含转移性 CRPC。这些改变与前列腺的特定治疗脆弱性相关癌症（PCa）细胞。具体来说，同源重组（HR）修复中的缺陷可以预测对抑制聚（ADP-核糖）聚合酶（PARP）。 PARP抑制剂（PARPi）是一种新型靶向药物该疗法通过阻止 PARP 酶修复肿瘤细胞中受损的 DNA 来发挥作用。乳腺癌1/2 编码 HR 修复必需的蛋白质。缺乏 BRCA1/2 的癌细胞反而依赖 PARP 调节 DNA 修复并对 PARPi 高度敏感。美国FDA已批准两种PARP抑制剂（olaparib和 rucaparib）用于治疗具有 HR 修复突变（或有害 BRCA）的转移性 CRPC 患者突变）基于最近的临床试验结果。使用 PARPi 进行有效治疗的主要障碍之一是如何选择最有可能的患者受益于 PARP 抑制。 BRCA 突变可以预测 PARPi 反应，准确度为 50-60%。然而，具有非 BCRA 基因组改变的患者对 PARPi 的反应程度仍不清楚。通过通过全基因组 CRISPR 筛选，我们最近发现 PCa 细胞中 RNASEH2B 的缺失可能预测对 PARP 抑制的反应。 RNASEH2B 是三个 RNase H2 亚基之一，被认为在DNA复制中发挥作用。最近的一项研究证明了其在核糖核苷酸切除修复中的功能，这可能会导致 PARP 捕获损伤。重要的是，TCGA 数据集的分析揭示了 RNASEH2B 17% 的 PCa 肿瘤存在深度缺失。染色体 13q14 上 RNASEH2B 和 RB1 频繁共缺失发生。此外，我们的 CRISPR 筛选结果进一步表明，TP53 的缺失可能会导致 PCa 细胞对 PARPi 产生耐药性。因此，该项目的目标是确定（1）损失程度 RNASEH2B 在临床前 PCa 模型中赋予 PARPi 细胞反应； (2) 失活程度 TP53 和 RB1 影响对 PARPi 的响应。该项目的成功实施将奠定未来在具有 RNASEH2B/TP53/RB1 改变的 PCa 患者中进行临床试验的阶段，并显着扩展符合 PARP 抑制条件的患者库。