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Assessing DNA polymerase theta as a therapeutic target in BRCA1 mutant cancer

评估 DNA 聚合酶 θ 作为 BRCA1 突变癌症的治疗靶点

基本信息

批准号：
10446399
负责人：
Neil Johnson
金额：
$ 43.01万
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/10446399
关键词：
Address Alleles BRCA mutations BRCA1 Mutation BRCA1 Protein BRCA1 gene BRCA2 Mutation Biological Assay Biological Factors Biological Markers Breast Cancer Patient Cancer cell line Cell Line Cells Cessation of life Chromosome Pairing Clinical Clinical Research Collaborations DNA DNA Repair DNA Repair Pathway DNA biosynthesis DNA sequencing DNA-Directed DNA Polymerase Data Dependence Drug resistance Event Excision Future Genetic Goals Human Immunofluorescence Microscopy In Vitro Knock-out Knockout Mice Knowledge Malignant Neoplasms Malignant neoplasm of ovary Measures Mediating Molecular Mutate Names Outcome Patients Pharmacology Polymerase Process Proteins Publishing Reporter Resistance Role Single-Stranded DNA Site Testing United States Work cancer therapy cell type clinical application homologous recombination in vivo inhibitor inhibitor therapy insight malignant breast neoplasm mutant nuclease patient derived xenograft model patient population patient stratification preclinical development refractory cancer repaired small molecule small molecule inhibitor therapeutic target therapeutically effective therapy development treatment strategy

项目摘要

PROJECT SUMMARY Genetic disruption of DNA polymerase theta (Polθ) activity has been shown to effectively target BRCA1 mutated cells, while leaving BRCA1 wild-type (WT) cells intact. Polθ facilitates theta-mediated DNA end joining (TMEJ) repair by promoting DNA synapsis and repair synthesis at break sites containing 3' single stranded (ss)DNA overhangs. Although small molecule inhibitors of Polθ activity are currently under development for the treatment of BRCA1 mutant cancers, very little is known regarding the mechanisms that activate TMEJ and result in Polθ- dependency in BRCA1 mutant cells. Moreover, the current paradigm assumes that homologous recombination (HR)-deficiency confers Polθi sensitivity, therefore PARPi responsiveness is expected to be a biomarker for Polθ inhibitor (Polθi) sensitivity. In our preliminary data, we unexpectedly identified commonly used Brca1 mutant cells that grow relatively unperturbed with genetic Polq (Polθ) knockout (KO), indicating that Polθi and PARPi sensitivity may not necessarily correlate. In this proposal, we will elucidate the molecular requirements for TMEJ activation and identify biological factors that distinguish PARPi and Polθi sensitivity. We will address the following Specific Aims: 1) reveal the molecular basis of TMEJ activation in Brca1 mutant cells; 2) uncover genetic Polθ- dependencies in Brca1 mutant cells; and 3) examine pharmacologic Polθ inhibition in Brca1 mutant cells. Collectively, these studies will be informative for future clinical studies employing Polθi.

项目概要 DNA 聚合酶 theta (Polθ) 活性的基因破坏已被证明可以有效靶向 BRCA1 突变细胞，同时保持 BRCA1 野生型 (WT) 细胞完整。 Polθ 促进 theta 介导的 DNA 末端连接 (TMEJ) 通过促进含有 3' 单链 (ss)DNA 的断裂位点的 DNA 突触和修复合成进行修复悬垂。尽管目前正在开发用于治疗的 Polθ 活性小分子抑制剂对于 BRCA1 突变癌症，我们对激活 TMEJ 并导致 Polθ- 的机制知之甚少 BRCA1 突变细胞的依赖性。此外，当前的范式假设同源重组 (HR) 缺乏赋予 Polθi 敏感性，因此 PARPi 反应性预计将成为 Polθ 的生物标志物抑制剂 (Polθi) 敏感性。在我们的初步数据中，我们意外地发现了常用的 Brca1 突变体基因 Polq (Polθ) 敲除 (KO) 后生长相对不受干扰的细胞，表明 Polθi 和 PARPi 敏感性可能不一定相关。在本提案中，我们将阐明 TMEJ 的分子要求激活并识别区分 PARPi 和 Polθi 敏感性的生物因素。我们将解决以下问题具体目标：1）揭示Brca1突变细胞中TMEJ激活的分子基础； 2）揭示遗传Polθ- Brca1 突变细胞的依赖性； 3) 检查 Brca1 突变细胞中的药理学 Polθ 抑制。总的来说，这些研究将为未来使用 Polθi 的临床研究提供信息。