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

研究项目3：优化DNA损伤修复靶向联合疗法

• 批准号: 10242642
• 负责人: FUNDA MERIC-BERNSTAM
• 金额: $ 21.81万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242642
• 关键词: BRCA mutations; Biological Markers; Biopsy; Cell Line; Cells; Clinical; Combined Modality Therapy; DNA Damage; DNA Repair; Data; Defect; Development; Disease; Early Therapeutic-Clinical Trials Network; Genomics; Genotype; Goals; KRAS2 gene; MAP Kinase Gene; MEKs; Modeling; Molecular; Mutation; Organoids; Pathway interactions; Patients; Phenotype; Poly(ADP-ribose) Polymerases; Research Project Grants; Resistance; Selection for Treatments; Signal Transduction; Stable Disease; Testing; Texas; Translating; Universities; Work; base; co-clinical trial; gene repair; inhibitor/antagonist; interest; investigator-initiated trial; molecular subtypes; mutant; novel; patient derived xenograft model; pharmacodynamic biomarker; pre-clinical; predicting response; predictive marker; refractory cancer; response; response biomarker; synergism; targeted agent; targeted treatment; therapy resistant; treatment optimization; tumor

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.

抽象的 人们对靶向 DNA 损伤修复 (DDR) 的兴趣越来越浓厚，但预测标记在很大程度上是 缺乏与靶向治疗的最佳组合尚未阐明。在初步研究中，我们 研究表明，聚（ADP-核糖）聚合酶（PARP）抑制剂不仅在 PDX 中具有抗肿瘤功效 具有种系 BRCA 突变的模型，以及具有其他种系或体细胞改变的 PDX 模型 DDR基因。此外，我们还证明 K-Ras 突变细胞系对 PARP 抑制剂具有抗性，并且 MEK 抑制剂增强 PARP 抑制剂的抗肿瘤功效。在其他工作中，我们发现有一个 DDR 基因突变患者的 PI3K 通路改变显着富集 (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记 DDR抑制剂，可用于开发合理的联合疗法。我们的长期目标是使用 每个患者肿瘤的分子特征，以优化治疗选择。作为 PDX 开发和试验 中心，我们期望建立一个大型 PDX 组来促进基因分型（和其他分子亚型）- 表型相关性。我们假设具有 DDR 缺陷的肿瘤更有可能从 DNA 中受益 损伤抑制剂（例如 PARP、ATR、Wee1），以及针对可操作的基因组协同改变和 适应性反应可能会增强抗肿瘤功效。