Research Project 3: Optimizing DNA damage repair-targeted combination therapy

摘要 人们对靶向DNA损伤修复(DDR)的兴趣与日俱增，然而预测标记在很大程度上 缺乏与靶向治疗的最佳组合尚未阐明。在初步研究中，我们 已证明聚腺苷二磷酸核糖聚合酶(PARP)抑制剂不仅在PDX中具有抗肿瘤效果 带有生殖系BRCA突变的模型，但也存在具有其他生殖系或体细胞变化的PDX模型 DDR基因。此外，我们还发现K-RAS突变型细胞系对PARP抑制剂具有耐药性，并且 MEK抑制剂可增强PARP抑制剂的抗肿瘤效果。在其他工作中，我们发现有一个 在DDR基因突变的患者中，PI3K通路改变显著丰富(p=0.008)。我们 提出临床和分子注释的PDX模型可以帮助识别反应的预测标记物 DDR抑制剂，可用于开发合理的联合疗法。我们的长期目标是利用 根据每个患者肿瘤的分子特征来优化治疗选择。作为PDX的开发和试用 中心，我们希望建立一个大型的PDX面板，以促进基因型(和其他分子亚型)- 表型相关。我们假设有DDR缺陷的肿瘤将更有可能从DNA中受益 损伤抑制剂(如PARP、ATR、Wee1)，以及靶向可操作的基因组共改变和 适应性反应可能会增强抗肿瘤的疗效。

Abstract There is growing interest in targeting DNA damage repair (DDR), however predictive markers are largely lacking and optimal combinations with targeted therapies have not been elucidated. In preliminary studies, we have shown that poly (ADP-ribose) polymerase (PARP) inhibitors have antitumor efficacy not only in PDX models with germline BRCA mutations, but also in PDX models with other germline or somatic alterations in DDR genes. Further, we have shown that K-Ras mutant cell lines are resistant to PARP inhibitors and that MEK inhibitors enhance the antitumor efficacy of PARP inhibitors. In other work, we have found that there is a significant enrichment of PI3K pathway alterations in patients with mutations in DDR genes (p=0.008). We propose that clinically and molecularly annotated PDX models can help identify predictive markers of response to DDR inhibitors and can be used to develop rational combination therapies. Our long term goal is to use molecular features of each patient’s tumor to optimize therapy selection. As a PDX development and trial center, we expect to build a large panel of PDXs to facilitate genotype (and other molecular subtype)- phenotype correlation. We hypothesize that tumors with DDR defects will be more likely to benefit from DNA damage inhibitors (such as PARP, ATR, Wee1), and that targeting actionable genomic co-alterations and adaptive responses may enhance anti-tumor efficacy.