POLQ Synthetic Lethality in HR-Deficient Pancreatic Adenocarcinoma

HR 缺陷型胰腺癌中的 POLQ 综合致死率

• 批准号: 10218126
• 负责人: DIANE M SIMEONE
• 金额: $ 69.03万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-16 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10218126
• 关键词: ATM deficient; ATM gene; BRCA1 gene; BRCA2 gene; Biological; Biological Models; Cancer Biology; Cell Line; Cells; Characteristics; Chemoresistance; Chemotherapy and/or radiation; Clinical; Combined Modality Therapy; Critical Pathways; Cytotoxic Chemotherapy; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Pathway; Data; Data Set; Defect; Development; Diagnosis; Disease; Double Strand Break Repair; Enzymes; Genes; Genetic; Genetically Engineered Mouse; Genome Stability; Genomics; Germ-Line Mutation; Goals; Growth; Human; Human Characteristics; Immune response; Immunotherapy; Ionizing radiation; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Modeling; Mus; Mutation; Nonhomologous DNA End Joining; Organoids; PALB2 gene; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Phenotype; Platinum; Poly(ADP-ribose) Polymerases; Polymerase; Recurrence; Refractory; Regimen; Resistance; Resistance development; Role; Stimulator of Interferon Genes; Subgroup; Testing; Therapeutic; Therapeutic Effect; Tumor-infiltrating immune cells; antitumor effect; base; brca gene; cell killing; chemotherapeutic agent; chemotherapy; clinical development; combinatorial; efficacy testing; homologous recombination; human model; immune activation; immune checkpoint blockade; in vivo; inhibitor/antagonist; knock-down; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutics; overexpression; pancreatic cancer cells; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; pancreatic tumorigenesis; patient derived xenograft model; recombinational repair; response; targeted treatment; therapeutic target; therapeutically effective; tumor; tumor growth; tumor microenvironment

Pancreatic ductal adenocarcinoma (PDA) is a highly lethal human malignancy, typically diagnosed at an advanced stage and known to be largely unresponsive to chemotherapy and ionizing radiation. Recent genomic characterization of PDA reveals that between 20-25 % of PDA harbor recurrent mutations in genes, including BRCA1/2, PALB2, and ATM, which are critical for homologous recombination (HR), an important form of DNA repair. In many patients, these may be germline mutations. This subgroup of PDAs, termed HR-deficient PDA, has emerged as a defined biological entity associated with increased chemoresistance and a more aggressive disease course. The defects in HR observed in these tumors impart cells with a specific vulnerability to PARP inhibitors and platinum-containing therapy. Still, as observed in the case of many other targeted therapies, only a fraction of HR-defective patient tumors respond to PARP inhibition. More so, many patients that initially respond eventually often develop resistance and progress. Therefore, novel therapies which can be effective against HR- defective PDA, alone or in combination with PARP inhibitors or other combinatorial regimens, are urgently needed. We have recently determined that inactivation of the HR pathway is associated with overexpression of polymerase theta (PolƟ, also known as POLQ) in PDA. POLQ is a key enzyme that regulates an alternative pathway of DNA repair, known as the alternative non-homologous end-joining (Alt-NHEJ) pathway. Data from our group indicates that in the setting of defective HR, Alt-NHEJ becomes a critical pathway responsible for the repair of DNA breaks. Furthermore, we show that POLQ inhibition in HR-defective tumor cells demonstrates a synthetic lethality phenotype, not observed in cells with intact HR. In this proposal, we present exciting new data that knockdown of POLQ is synthetically lethal in PDA cells deficient for Brca1, Brca2, Atm, and Palb2 genes. POLQ knockdown significantly inhibited growth of both Brca2- and Atm-deficient tumors cells in vivo. Further, POLQ knockdown significantly upregulated the cGAS-STING pathway in HR-deficient PDA and promoted T cell infiltration. Here, we plan to examine the unique role of POLQ in pancreatic cancer biology and its role as a novel therapeutic target in HR-defective pancreatic cancers. We will also evaluate the antitumor effect of combining POLQ inhibition with: i) current standard cytotoxic chemotherapies, ii) PARP inhibition, and iii) immunotherapy. An important goal of this proposal is to generate a set of data for proof-of-concept that targeting POLQ in a valuable therapeutic strategy in HR-defective pancreatic cancer, as POLQ inhibitors are currently in development for clinical use.

胰腺导管腺癌（PDA）是一种高度致命的人类恶性肿瘤，通常在 高级阶段，已知对化学疗法和电离辐射的反应很大。最近的基因组 PDA的表征表明，在包括 BRCA1/2，PALB2和ATM，这对于同源重组至关重要（HR），这是DNA的重要形式 维修。在许多患者中，这些可能是种系突变。 PDA的该亚组，称为HR缺陷PDA， 已成为与化学抗性增加相关的定义生物学实体，并且更具侵略性 疾病课程。 在这些肿瘤中观察到的人力资源缺陷赋予细胞具有特异性的PARP抑制剂的细胞和 含铂的疗法。尽管如此，如许多其他靶向疗法所观察到的，只有一小部分 HR缺乏症的患者肿瘤对PARP抑制作用反应。更重要的是，许多最初反应的患者 最终经常发展抵抗和进步。因此，可以有效防止HR-有效的新型疗法 PDA有缺陷，单独或与PARP抑制剂或其他组合方案结合在一起，紧急是 需要。 我们最近确定HR途径的失活与过表达有关 PDA中的聚合酶theta（Polɵ，也称为POLQ）。 POLQ是调节替代方案的关键酶 DNA修复的途径，称为替代性非理论端连接（ALT-NHEJ）途径。来自 我们的小组表明，在HR有缺陷的情况下，Alt-Nhej成为负责该的关键途径 DNA断裂的修复。此外，我们表明HR缺陷肿瘤细胞中的POLQ抑制作用表明 合成致死性表型，在完整HR的细胞中未观察到。在此提案中，我们提出令人兴奋的新数据 在缺乏BRCA1，BRCA2，ATT和PALB2基因的PDA细胞中，POLQ的敲低是致命的。 POLQ敲低会在体内显着抑制BRCA2-缺陷型肿瘤细胞的生长。更远， POLQ敲低显着更新了HR缺陷PDA中的CGAS-Sting途径并促进了T细胞 浸润。 在这里，我们计划研究POLQ在胰腺癌生物学中的独特作用及其作为新颖的作用 人力资源缺陷胰腺癌中的治疗靶标。我们还将评估组合的抗肿瘤效应 POLQ抑制：i）当前标准的细胞毒性化学疗法，ii）PARP抑制和III） 免疫疗法。该提案的一个重要目标是生成一组数据，以证明概念证明 针对POLQ在HR缺陷性胰腺癌中的有价值的治疗策略中，因为POLQ抑制剂是 目前正在开发临床用途。