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24小时内诊断， 晚期，已知对化疗和电离辐射基本无反应。最近的基因组 PDA的特征显示，20- 25%的PDA在基因中具有复发突变，包括 BRCA 1/2、PALB 2和ATM，它们对同源重组（HR）（DNA的一种重要形式）至关重要 修复.在许多患者中，这些可能是生殖系突变。这种PDA亚组，称为HR缺陷型PDA， 已经成为一种明确的生物实体，与增加的化疗耐药性和更具侵略性的 病程。 在这些肿瘤中观察到的HR缺陷赋予细胞对PARP抑制剂的特异性脆弱性， 含铂治疗尽管如此，正如在许多其他靶向治疗的情况下所观察到的那样，只有一小部分 HR缺陷型患者肿瘤对PARP抑制有反应。更重要的是，许多患者最初的反应 最终往往会产生抵抗和进步。因此，可以有效对抗HR的新疗法- 有缺陷的PDA，单独或与PARP抑制剂或其他组合方案组合，迫切需要 needed. 我们最近已经确定HR途径的失活与以下蛋白的过度表达有关： 聚合酶θ（Polymerase theta，也称为POLQ）。POLQ是一种关键酶， DNA修复途径，称为替代性非同源末端连接（Alt-NHEJ）途径。数据从 我们的小组指出，在有缺陷的人力资源的设置，Alt-NHEJ成为一个关键的途径，负责 修复DNA断裂此外，我们表明，在HR缺陷的肿瘤细胞中，POLQ抑制证明了 合成致死表型，在HR完整的细胞中没有观察到。在这个提议中，我们提出了令人兴奋的新数据 POLQ的敲除在Brca 1、Brca 2、Atm和Palb 2基因缺陷的PDA细胞中是合成致死的。 POLQ敲低显著抑制体内Brca 2和Atm缺陷肿瘤细胞的生长。此外，本发明的目的是， POLQ敲低显著上调HR缺陷PDA中的cGAS-STING通路，并促进T细胞增殖。 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，以及它作为一种新的 HR缺陷性胰腺癌的治疗靶点。我们还将评估联合使用 POLQ抑制：i）当前标准细胞毒性化疗，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用于概念验证的数据， 在HR缺陷性胰腺癌的有价值的治疗策略中靶向POLQ， 目前正在开发用于临床。