Mouse models of Kras-mutant colorectal cancer

项目摘要/摘要 每年有50,000多名美国人死于结直肠癌。以氟尿嘧啶为基础的治疗仍然是 在过去的五年中，没有被批准用于CRC的靶向治疗。 KRAS癌基因的突变激活--在40%以上的病例中发生--是 结直肠癌患者对常规和靶向治疗的内在和获得性耐药。因为没有 直接或间接针对K-RAS或其下游效应通路、KRAS突变的有效治疗 是结直肠癌治疗的单一最大障碍。 对癌症基因组的大规模测序表明，在这40%的表达 突变的K-RAS，KRAS等位基因的多样性比任何其他类型的癌症都要大。流行病学研究 证明存活率和对治疗的反应取决于患者的KRAS基因 癌症，提示K-Ras癌蛋白的不同突变形式可能表现出不同的致癌作用 属性。然而，等位基因特异性行为的实验验证从未实现过。我们将使用 主要的人类和小鼠有机化合物和转基因小鼠模型解决三个关键问题 与K-RAS致瘤性有关的问题：(1)K-RAS的不同突变形式在它们的能力上是相同的 促进结直肠癌的发生和发展？(2)KRAS和其他基因之间的相互作用 基因等位基因特异性？(3)K-RAS突变形式如何影响非细胞肿瘤微环境-- 以自主方式促进癌症进展？ 这项工作的最终目标是破译“KRAS等位基因密码”，以确定治疗 对表达特定K-RAS突变体的癌症有效的策略。精准医学，其中一个 医生根据患者癌症中突变的基因量身定做治疗方法，要求达到这个水平 了解，特别是对突变的癌蛋白，如K-RAS，不能用直接抑制物靶向。

Project Summary/Abstract Colorectal cancer (CRC) kills more than 50,000 Americans each year. Fluorouracil-based therapy remains the standard of care and there have been no targeted therapies approved for use in CRC in the past half decade. Mutational activation of the KRAS oncogene – which occurs more than in 40% of cases – is a major source of intrinsic and acquired resistance to both conventional and targeted therapies in CRC. Since there are no effective therapies that directly or indirectly target K-Ras or its downstream effector pathways, KRAS mutation is the single greatest barrier to medical treatment for CRC. Large scale sequencing of cancer genomes has revealed that, among those 40% of CRCs that express mutant K-Ras, the diversity of KRAS alleles is greater than in any other type of cancer. Epidemiological studies demonstrate that survival and response to therapy varies depending on the KRAS genotype of the patient's cancer, suggesting that different mutant forms of the K-Ras oncoprotein could exhibit distinct oncogenic properties. Experimental validation of allele-specific behaviors has never been achieved, however. We will use primary human and mouse organoids and genetically engineered mouse models to address three key questions relating to K-Ras oncogenicity: (1) Are different mutant forms of K-Ras equivalent in their ability to promote colorectal cancer initiation and progression? (2) Are genetic interactions between KRAS and other genes allele-specific? (3) How do mutant forms of K-Ras influence the tumor microenvironment in a non-cell- autonomous manner to promote cancer progression? The ultimate goal of this work is to decipher the “KRAS Allele Code” in order to identify therapeutic strategies that are effective for cancers expressing specific K-Ras mutants. Precision medicine, where a physician tailors a patient's therapy to the genes that are mutated in his/her cancer, requires this level of understanding, especially for mutant oncoprotein that, like K-Ras, cannot be targeted with direct inhibitors.