Defining and Targeting Homologous Recombination Deficiency in Breast Cancer

乳腺癌同源重组缺陷的定义和针对

• 批准号: 10237881
• 负责人: Simon N. Powell
• 金额: $ 46.53万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-13 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10237881
• 关键词: 4T1; Affect; Aging; Alleles; BRCA1 gene; BRCA2 gene; Back; Biological Process; Breast Cancer Model; Breast Cancer Patient; Breast Cancer Treatment; Breast Epithelial Cells; Breast cancer metastasis; CHEK2 gene; Cell Line; Cell Survival; Cells; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Complex; Correlative Study; Cytosine deaminase; Cytotoxic agent; DNA Damage; DNA Repair; DNA Repair Disorder; DNA Repair Pathway; DNA Sequence Alteration; Defect; Development; Disease; Double Strand Break Repair; Engineering; Estrogen receptor positive; Event; Excision; Frequencies; Gene Mutation; Genes; Genetic; Genome; Genomic Instability; Genomics; Genotype; Goals; Human; Immune checkpoint inhibitor; Immune system; Interruption; Lead; Length; Link; MCF10A cells; MCF7 cell; Malignant Neoplasms; Memorial Sloan-Kettering Cancer Center; Metastatic breast cancer; Methods; Mus; Mutation; New Agents; Non-Malignant; Nonhomologous DNA End Joining; PALB2 gene; Pathway interactions; Patient Selection; Patients; Pattern; Play; Prognosis; Proteins; Radiation therapy; Recovery; Role; Sequence Deletion; Signal Transduction; Specimen; Subgroup; System; T47D; Taxonomy; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; base; brca gene; breast cancer genomics; breast tumorigenesis; cytotoxic radiation; ds-DNA; gene repair; genetically modified cells; genome sequencing; genomic signature; homologous recombination; improved; improved outcome; inhibitor/antagonist; malignant breast neoplasm; mouse model; mutant; neoplastic cell; personalized medicine; pre-clinical; repaired; response; stem; targeted treatment; therapeutic target; treatment response; tumor; tumor DNA; whole genome

Abstract Homologous recombination deficiency is prevalent in breast cancer up to a level of ~25%. Large-scale alterations to the genome have been observed in these tumors, but if double-strand junctions are sequenced in addition, it is possible to categorize these tumors into upstream and downstream defects in the DNA repair pathway. We assert that there fundamentally different patterns of genome instability for double-strand break repair. One is focused on the function of the BRCA1-BRCA2 pathway, where alterations in function are rather frequent in breast cancers. Although traditionally perceived as equivalent, there is evidence to demonstrate that downstream alterations that are BRCA1-like may have genomic and functional differences from those that are BRCA2-like. Conversely, the upstream defects are focused on sensing DNA damage, which is another way to suppress cancer formation. Our hypothesis is that different types of DNA repair defects result in the utilization of distinct back-up DNA repair mechanisms, which themselves result in specific genomic signatures and sensitivity to different therapeutic agents. Hence, we posit that upstream defects are best targeted by the use of replication checkpoint inhibitors, but that BRCA defective tumors are best treated by targeting the backup pathway, such as PARP-inhibitors or new agents beyond PARP-inhibitors. The goal of the first aim is to apply the current genomic landscape tests of HR-deficiency and determine which method predicts most accurately the type of homologous recombination DNA repair defect. The ultimate goal is to devise a taxonomy based on the genomics features of homologous recombination DNA repair-deficiency, in addition to target gene mutations, which will ultimately guide therapeutic options. The second aim is to generate genetically engineered cell lines to understand the developmental drivers of the genomic landscape changes. In addition, we will use these cells to test new synthetic lethal approaches to target specific subsets of breast cancers with distinct types of homologous recombination DNA repair defects. The third aim consists of human clinical trials either being conducted at Memorial Sloan Kettering Cancer Center or elsewhere, where we are conducting the trial or leading the analysis of the clinical bio-specimens for correlative study analyses. We will study the impact of the PARP-inhibitor olaparib in patients who are BRCA1/2 wild-type but harbor a germline and/or somatic genetic alteration affecting homologous recombination DNA repair-related genes. We will extend our studies to also consider the combined effects of radiotherapy in combination with either ATR- inhibitors or PARP-inhibitors. The ultimate goal of this project is to personalize the treatment of breast cancer patients whose tumors display homologous recombination DNA repair-related defects according to their genetic and genomic features, seeking to substantially improve the outcome of these poor prognosis patients and direct the deployment of therapeutic agents either already approved (e.g. olaparib) or already in clinical trials (e.g. ATR-inhibitors).

抽象的 同源重组缺乏在乳腺癌中普遍存在，高达约25％。大规模 在这些肿瘤中已经观察到了基因组的改变，但是如果在 此外，可以将这些肿瘤分为DNA修复中的上游和下游缺陷 路径。我们断言，有根本不同的基因组不稳定性模式用于双链断裂 维修。一个专注于BRCA1-BRCA2途径的功能，其中功能的改变是 经常在乳腺癌中。尽管传统上被认为是同等的，但有证据表明 类似于BRCA1的下游变化可能与 类似于brca2。相反，上游缺陷专注于感应DNA损伤，这是另一种方式 抑制癌症的形成。我们的假设是不同类型的DNA修复缺陷导致 利用不同的备份DNA修复机制，这本身会导致特定的基因组特征 对不同治疗剂的敏感性。因此，我们认为上游缺陷是最好的目标 使用复制检查点抑制剂，但BRCA有缺陷的肿瘤可以通过靶向 备用途径，例如PARP抑制剂或PARP抑制剂以外的新代理。第一个目标的目标是 应用当前的HR缺乏基因组景观测试，并确定哪种方法预测了大多数方法 准确地类型的同源重组DNA修复缺陷。最终目标是设计一个 基于同源重组DNA修复缺陷的基因组学特征的分类法，此外 靶基因突变，最终将指导治疗选择。第二个目的是生成 基因工程细胞系，以了解基因组景观变化的发展驱动因素。 此外，我们将使用这些细胞测试新的合成致命方法来靶向乳腺的特定子集 具有不同类型的同源重组DNA修复缺陷的癌症。第三目由人类组成 临床试验要么是在纪念斯隆·克特林癌症中心或其他地方进行的临床试验 进行试验或领导临床生物特异性分析以进行相关研究分析。我们将 研究PARP抑制剂Olaparib对BRCA1/2野生型但具有种系的患者的影响 和/或体细胞遗传改变影响同源重组DNA修复相关基因。我们将 扩展我们的研究，以考虑放疗的综合作用与ATR- 抑制剂或PARP抑制剂。该项目的最终目标是个性化乳腺癌治疗 肿瘤表现出同源重组DNA修复缺陷的患者 遗传和基因组特征，旨在大大改善这些不良预后患者的结果 并指导已经批准的治疗剂的部署（例如Olaparib）或已经在临床上 试验（例如ATR抑制剂）。