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castration-耐药前列腺癌（MCRPC）是一种无法治愈的疾病，有望 在美国，每年约34,500人死亡。 MCRPC的治疗选择有限 延长寿命的患者。迫切需要开发新颖的目标疗法，尤其是 基于肿瘤基因组改变的个性化疗法。最近的基因组研究表明 具有潜在基因组改变的各种可作用的分子靶标。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，并丰富了 MCRPC。这些改变与前列腺癌的特殊治疗脆弱性有关 （PCA）细胞。具体而言，同源重组修复（HRR）的缺陷将预测对 抑制聚（ADP-核糖）聚合酶（PARP）。 PARP抑制剂（PARPIS）是一种新型的目标 治疗方法是防止酶PARP修复肿瘤细胞中受损受损的DNA的治疗。 BRCA1/2 编码HRR必不可少的蛋白质。缺乏BRCA1/2的癌细胞取决于PARP调节的DNA 维修，对Parpis高度敏感。美国FDA批准了两个PARP抑制剂（Olaparib和 rucaparib）基于HRR突变（或有害BRCA1/2突变）的MCRPC患者的治疗 最近的临床试验结果。 使用PARPI的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突变可以以50-60％的精度预测PARPI响应。 但是，非BCRA1/2基因组改变患者对PARPIS的响应程度仍然存在 不清楚。通过全基因组CRISPR筛选，我们最近发现PCA中MMS22L的损失 细胞预测对PARP抑制的反应。 MMS22L是复制叉相关DNA所需的 双链断裂。更重要的是，在前列腺肿瘤中经常删除MMS22L基因（约14％）。在 此外，我们的CRISPR筛查的结果进一步表明，TP53或RB1的损失可能会导致PCA 由于HRR基因表达的上调，细胞对PARPIS的抗性，可以通过合并来克服这些基因 ATR抑制。因此，该项目的目的是确定（1）MMS22L的损失在多大程度上赋予了A 临床前PCA模型中对PARP抑制的细胞反应； （2）TP53或RB1的灭活程度在多大程度上 影响PARPI响应； （3）ATR抑制在多大程度上重新敏感的PCA细胞对PARP 抑制。该项目的成功完成将为MCRPC患者的将来的临床试验奠定基础 使用MMS22L和TP53/RB1改变，并显着扩大合格患者的PARP 抑制。