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

• 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
• 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

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.

项目摘要/摘要 本申请是为了回应被确认为非CA-CA的特殊利益通知(NOSI)而提交的 23-064。BRCA1、PALB2和BRCA2(BRCA)胚系突变会增加乳房发育的终生风险 卵巢癌。BRCA缺陷细胞，无论是癌症还是癌前病变，都是同源定向修复(HDR)- 有缺陷的，因此对导致DNA损伤或抑制DNA修复的药物高度敏感。HDR活性丧失 提供治疗机会，例如，PARP抑制剂(PARPI)选择性地杀死HDR缺陷细胞和 被批准用于治疗BRCA突变的癌症。PARPI疗法，尽管在 癌症的治疗，并不是一种理想的预防性药物，因为治疗会引起恶心、疲劳和 骨髓抑制。因此，对阻止或拖延的新的预防性目标和制剂的需求尚未得到满足。 BRCA相关癌症的发展。在本补充资料中，我们将进行原则证明研究和 确定DNA聚合酶Theta(POLθ)是否是预防BRCA1癌症的有效靶点。我们会 使用卵巢癌小鼠模型来检测POLQ基因状态对BRCA1癌症发生的影响。 这些想法将在以下目标中得到检验：评估BRCA1癌症启动和POLQ基因突变。我们 将使用来自患有高级别浆液性卵巢癌(HGSOC)转基因小鼠的同基因小鼠模型 为了检查肿瘤的启动，这些初步研究将确定POLθ是否是治疗 并为未来使用小分子POLθ抑制剂的研究奠定基础。