Defining BRCA replication dysfunction in therapy response

定义治疗反应中的 BRCA 复制功能障碍

基本信息

批准号：
10190872
负责人：
Sharon B Cantor
金额：
$ 55.59万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
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：
2020-06-12 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10190872
关键词：
Ants BRCA deficient BRCA1 gene BRCA2 gene Biological Models Breast Cancer gene Cancer Patient Cells Chemoresistance Complex DNA DNA Double Strand Break DNA Repair DNA biosynthesis DNA replication fork Data Set Defect Degradation Pathway Development Double Strand Break Repair Filament Functional disorder Genes Genome Goals Grant Hereditary Breast Carcinoma Human Cell Line Hypersensitivity Kinetics Knowledge Malignant Neoplasms Maps Measures Mediating Modeling Molecular Mutagens Mutation Outcome Pathway interactions Patients Pharmaceutical Preparations Platinum Polymerase Proteins Proteomics Research Resistance Resistance development Ribose Sampling Single-Stranded DNA Source Stress Testing Transact Tumor Markers cancer cell chemotherapy effective therapy experimental study homologous recombination inhibitor/antagonist insight mutant patient response predictive marker prevent protein function resistance mechanism response restraint therapy resistant tissue culture tumor

项目摘要

The goal of this grant is to harness a new understanding of vulnerabilities in tumors with mutations in the hereditary breast cancer genes. We have found that cells deficient in the BRCA-pathway genes, fail to properly respond to DNA replication perturbations (stress) and consequently replication is not restrained properly and ssDNA regions (gaps) develop. We find that when gaps are present, BRCA cancer cells are sensitive to therapy and when gaps are avoided, resistance occurs. Our findings that gaps are fundamental to therapy response is a paradigm shift in the current framework that proposes that persistent DNA breaks and fork degradation is the cause of sensitivity. Thus, we propose to employ state-of-the-art experiments to map the molecular determinants of this BRCA pathway fork restraint function. Moreover, will identify the gap making machinery that is critical for therapy response and the gap avoidance machinery that is critical to therapy resistance. Lastly, we will re- examine models of therapy resistance previously attributed to restored DNA repair and fork protection and determine if gap suppression is instead the fundamental resistance mechanism. Collectively, these proposed studies will identify how cancer cells succumb to and eventually gain resistance to chemotherapy and provide valuable insight towards biomarkers predicting resistance and drugs that prevent resistance.

这笔赠款的目标是利用对具有突变的肿瘤的脆弱性的新认识遗传性乳腺癌基因。我们发现，缺乏 BRCA 途径基因的细胞无法正确地对 DNA 复制扰动（压力）做出反应，因此复制未得到适当限制， ssDNA 区域（间隙）形成。我们发现，当存在间隙时，BRCA 癌细胞对治疗敏感当避免出现间隙时，就会产生阻力。我们的发现是，差距是治疗反应的基础当前框架的范式转变，提出持续的 DNA 断裂和叉降解是敏感的原因。因此，我们建议采用最先进的实验来绘制分子决定因素该 BRCA 通路分叉抑制功能。此外，将确定对生产至关重要的间隙制造机制治疗反应和间隙避免机制对于治疗抵抗至关重要。最后，我们将重新检查先前归因于恢复的 DNA 修复和分叉保护的治疗抵抗模型确定缺口抑制是否是基本阻力机制。总的来说，这些提议研究将确定癌细胞如何屈服并最终获得对化疗的抵抗力，并提供对预测耐药性的生物标志物和预防耐药性的药物具有宝贵的见解。