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

摘要 人们对靶向DNA损伤修复（DDR）的兴趣越来越大，然而预测性标记物在很大程度上是不确定的。 缺乏与靶向治疗的最佳组合尚未阐明。在初步研究中，我们 已经显示聚（ADP-核糖）聚合酶（PARP）抑制剂不仅在PDX中具有抗肿瘤功效， 在具有生殖系BRCA突变的模型中，以及在具有其他生殖系或体细胞改变的PDX模型中， DDR基因。此外，我们已经表明K-Ras突变细胞系对PARP抑制剂具有抗性， MEK抑制剂增强PARP抑制剂的抗肿瘤功效。在其他工作中，我们发现， 在DDR基因突变的患者中，PI 3 K通路改变显著富集（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志物， DDR抑制剂，并可用于开发合理的联合治疗。我们的长期目标是利用 每个患者肿瘤的分子特征，以优化治疗选择。作为PDX开发和试用 中心，我们希望建立一个大面板的PDX，以促进基因型（和其他分子亚型）- 表型相关我们假设，DDR缺陷的肿瘤将更有可能受益于DNA 损伤抑制剂（如PARP、ATR、Wee 1），以及靶向可操作的基因组共改变和 适应性反应可增强抗肿瘤功效。

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.