POLQ Synthetic Lethality in HR-Deficient Pancreatic Adenocarcinoma

HR 缺陷型胰腺癌中的 POLQ 综合致死率

基本信息

批准号：
10442427
负责人：
DIANE M SIMEONE
金额：
$ 66.65万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
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/10442427
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 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

项目摘要

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，通常在晚期，已知对化疗和电离辐射基本上没有反应。 PDA 的特征表明，20-25% 的 PDA 存在反复出现的基因突变，包括 BRCA1/2、PALB2 和 ATM，对于同源重组 (HR)（DNA 的一种重要形式）至关重要在许多患者中，这些可能是种系突变，称为 HR 缺陷型 PDA。已成为一种与化学耐药性增加和更具侵袭性相关的明确生物实体病程。在这些肿瘤中观察到的 HR 缺陷使细胞对 PARP 抑制剂具有特定的脆弱性，并且然而，正如在许多其他靶向疗法中观察到的那样，含铂疗法仅占其中的一小部分。 HR 缺陷的患者肿瘤对 PARP 抑制有反应，更重要的是，最初许多患者都有反应。最终常常会产生耐药性并取得进展，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联合使用，是迫切需要解决的问题。需要。我们最近确定 HR 通路的失活与 PDA 中的聚合酶 theta（PolƟ，也称为 POLQ）是调节替代酶的关键酶。 DNA 修复途径，称为替代非同源末端连接 (Alt-NHEJ) 途径数据来自。我们的小组表明，在 HR 有缺陷的情况下，Alt-NHEJ 成为导致此外，我们发现 HR 缺陷肿瘤细胞中的 POLQ 抑制表现出合成致死表型，在具有完整 HR 的细胞中未观察到。在本提案中，我们提出了令人兴奋的新数据。在缺乏 Brca1、Brca2、Atm 和 Palb2 基因的 PDA 细胞中，POLQ 的敲低具有综合致死性。 POLQ 敲低显着抑制体内 Brca2 和 Atm 缺陷肿瘤细胞的生长。 POLQ 敲低显着上调 HR 缺陷 PDA 中的 cGAS-STING 通路并促进 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一种新型药物的作用我们还将评估联合用药的抗肿瘤作用。 POLQ 抑制：i) 当前标准细胞毒性化疗，ii) PARP 抑制，以及 iii) 该提案的一个重要目标是生成一组用于概念验证的数据靶向 POLQ 是 HR 缺陷型胰腺癌的一种有价值的治疗策略，因为 POLQ 抑制剂目前正在开发用于临床。