Assessing DNA Polymerase Theta as a Therapeutic Target in BRCA1 Mutant Cancer

评估 DNA 聚合酶 Theta 作为 BRCA1 突变癌症的治疗靶点

基本信息

批准号：
10884036
负责人：
Neil Johnson
金额：
$ 20万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10884036
关键词：
Alleles BRCA deficient BRCA1 Mutation BRCA1 gene BRCA2 Mutation BRCA2 gene Breast Cells Cessation of life Chemoprevention Clinical Trials Complement DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Disorder DNA Repair Enzymes DNA Repair Gene DNA Repair Inhibition DNA-Directed DNA Polymerase Dependence Development Digestion Double Strand Break Repair Drug Targeting Early Intervention Excision Fatigue Funding Future Gene Mutation Genes Genotype Germ-Line Mutation Goals Grant Heritability High-Risk Cancer Image Longevity Loss of Heterozygosity Malignant Neoplasms Malignant neoplasm of ovary Mediating Molecular Target Monitor Mus Myelosuppression Nausea Normal Cell Organ Ovarian PALB2 gene Parents Patients Pharmaceutical Preparations Phase Pilot Projects Poly(ADP-ribose) Polymerase Inhibitor Polymerase Predisposition Prevention strategy Proteins Publishing Research Personnel Role Serous Specialized Center Testing Therapeutic Transgenic Mice United States Validation Wild Type Mouse Work cancer cell cancer initiation cancer prevention cancer therapy cell type design efficacy evaluation helicase high risk population inhibitor inhibitor therapy interest lifetime risk luminescence malignant breast neoplasm mouse model mutant neoplastic novel nuclease premalignant prevent repaired response small molecule small molecule inhibitor therapeutic target tumor initiation tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 23-064. BRCA1, PALB2, and BRCA2 (BRCA) germline mutations increase lifetime risk of developing breast and ovarian cancer. BRCA-deficient cells, whether cancer or pre-cancer, are homology directed repair (HDR)- defective and thus highly sensitive to drugs that cause DNA damage or inhibit DNA repair. Loss of HDR activity provides therapeutic opportunities, for example, PARP inhibitors (PARPi) selectively kill HDR-deficient cells and are approved to treat BRCA-mutant cancers. PARPi therapy, although generally well-tolerated in the setting of cancer treatment, is not an ideal preventative agent, given therapy causes nausea, fatigue and myelosuppression. Therefore, there is an unmet need for new preventative targets and agents that block or delay the development of BRCA-associated cancer. In this supplement, we will carry out proof-of-principle studies and determine whether DNA Polymerase Theta (Polθ) is an effective target for BRCA1 cancer prevention. We will use an ovarian cancer mouse model to examine the impact of Polq gene status on Brca1 cancer development. These ideas will be tested in the following Aim: Evaluate Brca1 cancer initiation and Polq gene mutations. We will use a syngeneic mouse model derived from transgenic mice with high-grade serous ovarian cancer (HGSOC) to examine tumor initiation These preliminary studies will determine whether Polθ is an effective target for the interception and lay the ground work for future studies using small molecule Polθ inhibitors.

项目概要/摘要本申请是为了响应被识别为 NOT-CA- 的特殊利益通知 (NOSI) 而提交的 23-064。BRCA1、PALB2 和 BRCA2 (BRCA) 种系突变会增加终生患乳腺癌的风险。卵巢癌缺陷细胞，无论是癌症还是癌前病变，都是同源定向修复（HDR）- 有缺陷，因此对导致 DNA 损伤或抑制 HDR 活性丧失的药物高度敏感。提供治疗机会，例如，PARP 抑制剂 (PARPi) 选择性杀死 HDR 缺陷细胞， PARPi 疗法被批准用于治疗 BRCA 突变癌症，尽管在以下情况下通常耐受性良好。癌症治疗不是理想的预防剂，治疗会导致恶心、疲劳和因此，对阻断或延迟骨髓抑制的新预防靶点和药物的需求尚未得到满足。在本补充材料中，我们将开展原理验证研究并研究 BRCA 相关癌症的发展。确定 DNA 聚合酶 Theta (Polθ) 是否是 BRCA1 癌症预防的有效靶标。使用卵巢癌小鼠模型来检查 Polq 基因状态对 Brca1 癌症发展的影响。这些想法将在以下目标中得到检验：评估 Brca1 癌症起始和 Polq 基因突变。将使用源自患有高级别浆液性卵巢癌（HGSOC）的转基因小鼠的同基因小鼠模型检查肿瘤的起始这些初步研究将确定 Polθ 是否是肿瘤的有效靶点拦截并为未来使用小分子 Polθ 抑制剂的研究奠定基础。