Modeling KRAS genetic heterogeneity in mouse models

在小鼠模型中建立 KRAS 遗传异质性模型

• 批准号: 9195712
• 负责人: Kevin Haigis
• 金额: $ 55.7万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-15 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9195712
• 关键词: Alleles; American; American Society of Clinical Oncology; Animals; Antibodies; Biological Assay; Biological Response Modifier Therapy; Biology; Cancer Model; Cancer Patient; Cessation of life; Cetuximab; Clinical; Collaborations; Colon; Colorectal Cancer; Core Facility; Data; Diagnosis; Drug Combinations; Enterobacteria phage P1 Cre recombinase; Environment; Epidermal Growth Factor Receptor; Event; FDA approved; Frequencies; Genes; Genetic; Genetic Engineering; Genetic Heterogeneity; Genetic Transcription; Genetic Variation; Genetically Engineered Mouse; Genets; Goals; Human; Individual; Introns; Israel; K-ras mouse model; KRAS2 gene; Malignant Neoplasms; Measures; Medical Oncology; Medical center; Memorial Sloan-Kettering Cancer Center; Modeling; Molecular; Mus; Mutation; Oncoproteins; Other Genetics; Patients; Pharmacogenetics; Phenotype; Proteomics; Resistance; Sample Size; Series; Subgroup; Testing; Therapeutic; Therapeutic Studies; Tissues; Work; base; cohort; colon cancer patients; conventional therapy; design; efficacy study; efficacy testing; inhibitor/antagonist; mouse model; mutant; mutant mouse model; phosphoproteomics; pre-clinical; preclinical evaluation; preclinical study; preclinical trial; protein biomarkers; public health relevance; response; small molecule; targeted treatment; therapeutic evaluation; therapy resistant; treatment response; tumor; whole genome

 DESCRIPTION (provided by applicant): More than 140,000 Americans are diagnosed with colorectal cancer (CRC) each year and almost 52,000 individuals die from it. Decreasing the frequency of CRC-related death will undoubtedly require tailoring an individual's treatment to the specific mutations that have occurred in their cancer. Activating mutations in the K-Ras oncoprotein are common in CRC and are associated with particularly poor response to both conventional and targeted therapies. For example, the strong association between mutant K-Ras and resistance to anti-EGFR therapy led the American Society for Clinical Oncology to recommend that all cancer patients undergo K-Ras mutation testing prior to receiving treatment. Nevertheless, new clinical and experimental data have called into question the universality of therapeutic resistance associated with mutant K-Ras. Patients with specific K-Ras activating mutations, such as G13D, appear to benefit from anti-EGFR therapy, just like K-Ras wild-type patients. Building upon our expertise in studying Ras-mutant CRC in mouse models (Haigis et al. Nat. Genet. 40: 600-608, 2008; Wang et al. Cancer Disc. 3: 294-307, 2013), we will perform an in-depth analysis of the relationship between specific K-Ras mutations and therapeutic response. This work is separated into four related specific aims: (1) To comprehensively characterize the K-Ras mutational spectrum and to identify co-occurring mutations in primary human CRCs, (2) To generate an allelic series of Cre-dependent K-Ras activating alleles in mice, (3) To measure the molecular, cellular, and tissue-level phenotypes associated with different K-Ras mutations in a mouse model of CRC, and (4) To evaluate the efficacy of EGFR and MEK inhibitors in mouse models of CRC expressing different mutant alleles of K-Ras. In the end, the K-Ras mutant mouse models developed in this project will reveal genetic subpopulations of CRC patients that will benefit from specific targeted therapies.

 描述(申请人提供)：每年有超过140,000名美国人被诊断出患有结直肠癌(CRC)，近52,000人死于此病。减少结直肠癌相关死亡的频率无疑需要针对癌症中发生的特定突变量身定做个人的治疗。K-RAS癌蛋白的激活突变在结直肠癌中很常见，与对常规和靶向治疗的反应特别差有关。例如，突变的K-RAS与抗EGFR治疗耐药性之间的强烈关联导致美国临床肿瘤学学会建议所有癌症患者在接受治疗之前进行K-RAS突变检测。然而，新的临床和实验数据质疑了与突变K-RAS相关的治疗耐药的普遍性。具有特定K-RAS激活突变的患者，如G13D，似乎从抗EGFR治疗中受益，就像K-RAS野生型患者一样。基于我们在小鼠模型中研究RAS突变的CRC的专业知识(Haigis等人。纳特。吉内。2008年，40：600-608；Wang等人。癌症光盘。3：294-307,2013)，我们将深入分析特定K-RAS突变与疗效之间的关系。这项工作分为四个相关的具体目标：(1)全面表征K-RAS突变谱并鉴定原代人类CRC中的共生突变，(2)在小鼠中产生一系列依赖CRE的K-RAS激活等位基因，(3)在小鼠结直肠癌模型中测量与不同K-RAS突变相关的分子、细胞和组织水平的表型，以及(4)评估EGFR和MEK抑制剂在表达不同K-RAS突变等位基因的结直肠癌小鼠模型中的疗效。最后，在该项目中开发的K-RAS突变小鼠模型将揭示将受益于特定靶向治疗的结直肠癌患者的遗传亚群。