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

项目总结/摘要 本申请是为了响应被标识为NOT-CA的特别利益通知（NOSI）而提交的- 23-064. BRCA 1、PALB 2和BRCA 2（BRCA）生殖系突变会增加乳腺癌的终生风险， 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， 被批准用于治疗BRCA突变型癌症PARPi治疗，尽管在以下情况下通常耐受良好： 癌症治疗，不是一种理想的预防剂，给予治疗会引起恶心，疲劳和 骨髓抑制因此，对于阻断或延迟肿瘤生长的新的预防性靶标和药剂存在未满足的需求。 BRCA相关癌症的发展。在本附录中，我们将进行原理验证研究， 确定DNA聚合酶θ（Polθ）是否是BRCA 1癌症预防的有效靶点。我们将 使用卵巢癌小鼠模型研究Polq基因状态对Brca 1癌症发展的影响。 这些想法将在以下目标中进行测试：评估Brca 1癌症起始和Polq基因突变。我们 将使用来自高级别浆液性卵巢癌（HGSOC）转基因小鼠的同基因小鼠模型 这些初步研究将确定Polθ是否是肿瘤发生的有效靶点。 为今后使用小分子Polθ抑制剂进行研究奠定了基础。

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.