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: 10478008
• 负责人: Simon N. Powell
• 金额: $ 44.91万
• 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/10478008
• 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; 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; malignant breast neoplasm; mouse model; mutant; neoplastic cell; patient prognosis; 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 同源重组缺陷在乳腺癌中普遍存在，高达~25%。大规模 在这些肿瘤中观察到基因组的改变，但如果双链连接在 此外，还可以将这些肿瘤分为DNA修复的上游缺陷和下游缺陷 途径。我们断言，双链断裂的基因组不稳定性存在根本不同的模式 维修。一是关注 BRCA1-BRCA2 通路的功能，其中功能的改变相当明显。 常见于乳腺癌。尽管传统上被认为是等效的，但有证据表明 类似 BRCA1 的下游改变可能与那些类似 BRCA1 的下游改变具有基因组和功能差异 是 BRCA2 样的。相反，上游缺陷集中于感测DNA损伤，这是另一种方式 以抑制癌症的形成。我们的假设是不同类型的 DNA 修复缺陷会导致 利用不同的备份 DNA 修复机制，其本身会产生特定的基因组特征 以及对不同治疗药物的敏感性。因此，我们认为上游缺陷最好是由 使用复制检查点抑制剂，但 BRCA 缺陷肿瘤的最佳治疗方法是靶向 备用途径，例如 PARP 抑制剂或 PARP 抑制剂以外的新药物。第一个目标的目标是 应用当前 HR 缺陷的基因组景观测试并确定哪种方法预测效果最好 准确判断同源重组DNA修复缺陷的类型。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学，除了 目标基因突变，最终将指导治疗选择。第二个目标是产生 基因工程细胞系以了解基因组景观变化的发育驱动因素。 此外，我们将使用这些细胞来测试新的合成致死方法，以针对特定的乳腺亚群 具有不同类型同源重组 DNA 修复缺陷的癌症。第三个目标是人类 临床试验正在纪念斯隆凯特琳癌症中心或我们所在的其他地方进行 进行试验或领导临床生物样本分析以进行相关研究分析。我们将 研究 PARP 抑制剂奥拉帕尼对 BRCA1/2 野生型但具有种系的患者的影响 和/或影响同源重组DNA修复相关基因的体细胞遗传改变。我们将 扩大我们的研究范围，考虑放疗与 ATR 组合的综合效应 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 修复相关缺陷的患者 遗传和基因组特征，寻求显着改善这些预后不良患者的结果 并指导已批准（例如奥拉帕尼）或已进入临床的治疗药物的部署 试验（例如 ATR 抑制剂）。