MMS22L loss and PARP inhibition in prostate cancer

前列腺癌中 MMS22L 缺失和 PARP 抑制

• 批准号: 10635264
• 负责人: Li Jia
• 金额: $ 40.95万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10635264
• 关键词: Androgen Receptor; Armenia; BRCA1 Mutation; BRCA1 gene; BRCA2 Mutation; BRCA2 gene; Biological Markers; CRISPR screen; CRISPR/Cas technology; Cancer Patient; Cell Death; Cells; Cessation of life; Clinical; Clinical Trials; Complex; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Sequence Alteration; DNA lesion; DNA replication fork; Defect; Disease; E2F transcription factors; Eligibility Determination; Enzymes; Event; Filament; Future; G2/M Checkpoint Pathway; Gene Expression; Generations; Genes; Genetic; Genomics; Goals; Life; Malignant neoplasm of prostate; Measures; Mediating; Mitotic; Molecular Target; Mutation; Oncology; Outcome; Pathway interactions; Patient Selection; Patients; Poly(ADP-ribose) Polymerase Inhibitor; Poly(ADP-ribose) Polymerases; Prostatic Neoplasms; Proteins; RB1 gene; Receptor Signaling; Research; Resistance; Resolution; Site; TP53 gene; Testing; Therapeutic; Time; United States; Up-Regulation; Work; abiraterone; cancer cell; castration resistant prostate cancer; effective therapy; enzalutamide; gene discovery; gene repair; genome-wide; homologous recombination; improved; inhibitor; men; neoplastic cell; new therapeutic target; novel; personalized medicine; pre-clinical; predicting response; prevent; prostate cancer cell; prostate cancer model; recombinational repair; response; screening; targeted treatment; tumor

ABSTRACT Metastatic castration-resistant prostate cancer (mCRPC) is an incurable disease that is expected to account for ~ 34,500 deaths each year in the United States. Therapeutic options are limited for mCRPC 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 mCRPC. These alterations have been correlated with particular therapeutic vulnerabilities in prostate cancer (PCa) cells. Specifically, defects in homologous recombination repair (HRR) would predict sensitivity to inhibition of Poly (ADP-ribose) polymerase (PARP). PARP inhibitors (PARPis) 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 HRR. Cancer cells lacking BRCA1/2 depend instead on PARP-regulated DNA repair and are hypersensitive to PARPis. The U.S. FDA has approved two PARP inhibitors (olaparib and rucaparib) for treatment of mCRPC patients with HRR mutations (or deleterious BRCA1/2 mutations) based on the results from recent clinical trials. One of the major barriers to effective treatment using PARPis is how to select patients who most likely benefit from PARP inhibition. BRCA1/2 mutations can predict PARPi response with 50-60% accuracy. However, the degree to which patients with non-BCRA1/2 genomic alterations respond to PARPis remains unclear. Through genome-wide CRISPR screening, we have recently discovered that loss of MMS22L in PCa cells predicts the response to PARP inhibition. MMS22L is required for HRR of replication fork-associated DNA double strand breaks. More importantly, the MMS22L gene is frequently deleted (~14%) in prostate tumors. In addition, the results from our CRISPR screening further suggest that loss of TP53 or RB1 may render PCa cells resistance to PARPis due to upregulation of HRR gene expression, which can be overcome by combining ATR inhibition. Therefore, the goal of this project is to determine (1) to what extent loss of MMS22L confers a cellular response to PARP inhibition in preclinical PCa models; (2) to what extent inactivation of TP53 or RB1 influences PARPi response; (3) to what extent ATR inhibition re-sensitizes resistant PCa cells to PARP inhibition. The successful completion of this project will set the stage for future clinical trials in mCRPC patients with MMS22L and 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（mCRPC）是一种无法治愈的疾病，预计 美国每年约有 34,500 人死亡。 mCRPC 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 mCRPC。这些改变与前列腺癌的特定治疗脆弱性相关 (PCa) 细胞。具体来说，同源重组修复（HRR）的缺陷可以预测对 抑制聚（ADP-核糖）聚合酶（PARP）。 PARP抑制剂（PARPis）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 HRR 必需的蛋白质。缺乏 BRCA1/2 的癌细胞转而依赖 PARP 调节的 DNA 修复并对 PARPis 过敏。美国FDA已批准两种PARP抑制剂（olaparib和 rucaparib）用于治疗具有 HRR 突变（或有害的 BRCA1/2 突变）的 mCRPC 患者 最近的临床试验结果。 使用 PARPis 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。 BRCA1/2 突变可以预测 PARPi 反应，准确度为 50-60%。 然而，具有非 BCRA1/2 基因组改变的患者对 PARPis 的反应程度仍然存在 不清楚。通过全基因组 CRISPR 筛选，我们最近发现 PCa 中 MMS22L 的缺失 细胞预测对 PARP 抑制的反应。复制叉相关 DNA 的 HRR 需要 MMS22L 双链断裂。更重要的是，MMS22L 基因在前列腺肿瘤中经常被删除（~14%）。在 此外，我们的 CRISPR 筛选结果进一步表明，TP53 或 RB1 的缺失可能会导致 PCa 细胞对 PARP 的抵抗是由于 HRR 基因表达的上调，可以通过组合来克服 ATR 抑制。因此，该项目的目标是确定 (1) MMS22L 的损耗在多大程度上会导致 临床前 PCa 模型中 PARP 抑制的细胞反应； (2) TP53或RB1失活到什么程度 影响 PARPi 反应； (3) ATR 抑制在多大程度上使耐药 PCa 细胞对 PARP 重新敏感 抑制。该项目的成功完成将为未来针对 mCRPC 患者的临床试验奠定基础 具有 MMS22L 和 TP53/RB1 改变，并显着扩大符合 PARP 资格的患者群体 抑制。