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Mouse models of Kras-mutant colorectal cancer

Kras 突变结直肠癌小鼠模型

基本信息

批准号：
10640933
负责人：
Kevin Haigis
金额：
$ 62.68万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10640933
关键词：
Address Affect Agonist Alleles American Behavior Biochemical Bioinformatics Biological Biology Cancer Patient Cell physiology Cells Clinical Clinical Data Clinical Trials Code Codon Nucleotides Colorectal Cancer Complex Data Data Set Disease Engineering Epidemiology Epithelial Cells Exhibits Exposure to FDA approved Fluorouracil Frequencies Genes Genetic Genetic Engineering Genetic Screening Genetically Engineered Mouse Goals Grant Growth Human Immune Immunotherapy K-ras mouse model KRAS2 gene Knowledge Large-Scale Sequencing MCC gene Malignant Neoplasms Medical Medical Oncology Missense Mutation Molecular Mus Mutate Mutation Oncogenes Oncogenic Oncoproteins Organoids Outcome Pathway interactions Patients Physicians Population Primary Neoplasm Property Proteomics Receptor Signaling Resistance Shapes Signal Pathway Signal Transduction Source System Therapeutic Toll-like receptors Tumor Suppressor Genes United States Validation Work cancer genome cancer initiation cancer therapy cancer type checkpoint therapy colorectal cancer progression colorectal cancer treatment conventional therapy drug sensitivity effective therapy epidemiologic data epidemiology study genotyped patients immune function immunomodulatory therapies inhibitor mouse model mutant novel therapeutic intervention novel therapeutics precision medicine ras Proteins response standard of care targeted treatment treatment response tumor tumor growth tumor microenvironment tumor progression tumorigenesis

项目摘要

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.

项目总结/摘要结直肠癌（CRC）每年导致超过50，000名美国人死亡。氟尿嘧啶为基础的治疗仍然是在过去的五年中，没有批准用于CRC的靶向治疗。 KRAS癌基因的突变激活-发生在40%以上的病例中-是癌症的主要来源。对CRC中常规和靶向治疗的内在和获得性耐药性。由于没有直接或间接靶向K-Ras或其下游效应子通路、KRAS突变的有效疗法是CRC治疗的最大障碍。癌症基因组的大规模测序显示，在表达在突变型K-Ras中，KRAS等位基因的多样性大于任何其他类型的癌症。流行病学研究表明生存率和对治疗的反应取决于患者的KRAS基因型。这表明K-Ras癌蛋白的不同突变形式可以表现出不同的致癌性，特性.然而，等位基因特异性行为的实验验证从未实现。我们将使用主要的人类和小鼠类器官和基因工程小鼠模型，以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方面是否等同，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等位基因特异性基因(3)K-Ras的突变形式如何影响非细胞肿瘤微环境？自主的方式来促进癌症的进展？这项工作的最终目标是破译“KRAS等位基因密码”，以确定治疗性的对表达特定K-Ras突变体的癌症有效的策略。精准医疗，医生根据患者癌症中突变的基因量身定制患者的治疗，需要这种水平的理解，特别是对于突变癌蛋白，如K-Ras，不能用直接抑制剂靶向。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Learning from the nexus of autoimmunity and cancer.

DOI：
10.1016/j.immuni.2023.01.022
发表时间：
2023-02
期刊：
Immunity
影响因子：
32.4
作者：
D. Mangani;Dandan Yang;A. Anderson
通讯作者：
D. Mangani;Dandan Yang;A. Anderson

Allosteric Regulation of Switch-II Domain Controls KRAS Oncogenicity.

Switch-II 结构域的变构调节控制 KRAS 致癌性。

DOI：
10.1158/0008-5472.can-22-3210
发表时间：
2023
期刊：
Cancer research
影响因子：
11.2
作者：
Yang,MoonHee;Tran,TimothyH;Hunt,Bethany;Agnor,Rebecca;Johnson,ChristianW;Shui,Bing;Waybright,TimothyJ;Nowak,JonathanA;Stephen,AndrewG;Simanshu,DhirendraK;Haigis,KevinM
通讯作者：
Haigis,KevinM

Classification of KRAS-Activating Mutations and the Implications for Therapeutic Intervention.

DOI：
10.1158/2159-8290.cd-22-0035
发表时间：
2022-04-01
期刊：
Cancer discovery
影响因子：
28.2
作者：
Johnson C;Burkhart DL;Haigis KM
通讯作者：
Haigis KM

Regulation of GTPase function by autophosphorylation.

DOI：
10.1016/j.molcel.2022.02.011
发表时间：
2022-03-03
期刊：
Molecular cell
影响因子：
16
作者：
Johnson CW;Seo HS;Terrell EM;Yang MH;KleinJan F;Gebregiworgis T;Gasmi-Seabrook GMC;Geffken EA;Lakhani J;Song K;Bashyal P;Popow O;Paulo JA;Liu A;Mattos C;Marshall CB;Ikura M;Morrison DK;Dhe-Paganon S;Haigis KM
通讯作者：
Haigis KM