Defining and Targeting Homologous Recombination Deficiency in Breast Cancer

摘要 同源重组缺陷在乳腺癌中普遍存在，高达~ 25%的水平。大规模 在这些肿瘤中已经观察到基因组的改变，但是如果双链连接被测序， 此外，可以将这些肿瘤分类为DNA修复中的上游和下游缺陷， 通路我们断言，有根本不同的模式的基因组不稳定性的双链断裂 修复.一个是关注BRCA 1-BRCA 2通路的功能，其中功能的改变是相当重要的。 常见于乳腺癌。虽然传统上被认为是等同的，但有证据表明， BRCA 1样的下游改变可能与那些 是BRCA 2型的相反，上游的缺陷集中在传感DNA损伤，这是另一种方式 来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，其本身导致特定的基因组签名 和对不同治疗剂的敏感性。因此，我们认为上游缺陷最好由 使用复制检查点抑制剂，但BRCA缺陷型肿瘤的最佳治疗方法是靶向 备用途径，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 应用目前HR缺乏的基因组景观测试，并确定哪种方法预测最多 准确的同源重组DNA修复缺陷的类型。最终目标是设计一个 根据同源重组DNA修复缺陷的基因组学特征进行分类，此外， 靶向基因突变，这将最终指导治疗选择。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，以靶向乳腺癌的特定亚群。 具有不同类型的同源重组DNA修复缺陷的癌症。第三个目标是人 临床试验在纪念斯隆凯特琳癌症中心或其他地方进行， 开展试验或领导临床生物样本的分析，以进行相关研究分析。我们将 研究PARP抑制剂奥拉帕尼对BRCA 1/2野生型但含有生殖系的患者的影响 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 扩展我们的研究，也考虑放射治疗与ATR- 抑制剂或PARP抑制剂。这个项目的最终目标是个性化治疗乳腺癌 肿瘤显示同源重组DNA修复相关缺陷的患者， 遗传和基因组特征，寻求实质性改善这些预后不良患者的结果 并指导已经批准（例如奥拉帕尼）或已经进入临床的治疗药物的部署 试验（例如ATR抑制剂）。

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).