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Genetics and Biology of Metastatic Colorectal Cancer

转移性结直肠癌的遗传学和生物学

基本信息

批准号：
10474624
负责人：
RONALD ANTHONY DEPINHO
金额：
$ 38.18万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10474624
关键词：
Alleles Antitumor Response Automobile Driving Biology CCR5 gene CXCL3 gene Cancer Etiology Cataloging Cells Cessation of life Colon Carcinoma Colorectal Cancer Combined Modality Therapy Cytometry Cytotoxic T-Lymphocytes Data Dependence Disease Down-Regulation Doxycycline Drug Combinations Engineering Genes Genetic Genetic Epistasis Genomics Goals Human IL8RB gene Immune Immune Targeting Immunophenotyping Immunosuppression Interferon Suppression Interferons KRAS oncogenesis Malignant neoplasm of prostate Mediating Microsatellite Repeats Modeling Mus Mutation Myeloid-derived suppressor cells Neoplasm Metastasis Pathway interactions Pattern Population RANTES Repression Resistance Role Signal Pathway Signaling Molecule TP53 gene Testing Therapeutic Effect Transforming Growth Factor beta Treatment Efficacy Tumor-infiltrating immune cells United States Woman Work adenoma advanced disease anti-PD-1 base cancer cell cancer genomics chemokine chemokine receptor colon cancer patients colon cancer treatment colorectal cancer progression gene network human model immune checkpoint blockade immunoregulation improved inhibitor men metastatic colorectal molecular array mortality mouse model novel preclinical trial prognostic recruit response targeted agent therapeutically effective treatment response trial design tumor tumor microenvironment tumor progression

项目摘要

Abstract/Summary This proposal aims to dissect the actions of oncogenic KRAS (Kras*) its circuitry in controlling CRC immune biology with the goal of illuminating effective therapeutic strategies for testing in CRC patients. An array of molecular and pathobiological analyses comparing Kras* `on' versus Kras* `off' states in our mouse model of human CRC has revealed that Kras* drives and maintains invasive and metastatic disease, with Kras* expression correlating with a significant increase in myeloid derived suppressor cells (MDSCs) and decrease in killer T-cells. Preliminary mechanistic studies have shown that Kras* activates TGFβ, which in turn represses IRF2 (a master interferon regulatory factor), resulting in suppression of interferon response. The interferon network normally functions to promote anti-tumor responses. Thus, our overall goal in this study is to evaluate two hypotheses: (1) that Kras*/TGFβ-mediated repression of IRF2 creates an immune suppressive tumor microenvironment enabling cancer progression, and (2) that Kras*-driven immune suppression may provide a basis for the de novo resistance to immune checkpoint blockade (ICB) therapy observed in the majority of CRC patients. To achieve these goals, we propose the following Specific Aims: In Aim 1, we will characterize the immune suppressive cell subtypes driven by Kras* in primary CRC utilizing our novel CRC mouse model, and evaluate the effects of Kras* mutation on MDSC and TAM activities to identify the signaling molecules governing immune suppression in these tumors. In Aim 2, we will determine the mechanism by which TGFβ suppresses IRF2, and identify the immune circuits regulated by IRF2 in Kras*-driven CRC that may contribute to an immune suppressive tumor microenvironment enabling cancer progression. In Aim 3, we will investigate whether the neutralization of key Kras*-regulated targets in CRC can reverse primary resistance to immune checkpoint blockade therapy. Collectively, this proposal aims to identify novel combinations to improve the ICB sensitivity in Kras* CRC.

摘要/总结该提案旨在剖析致癌 KRAS (Kras*) 其电路在控制 CRC 免疫中的作用生物学的目标是阐明对 CRC 患者进行检测的有效治疗策略。一个数组在我们的小鼠模型中比较 Kras*“开启”与 Kras*“关闭”状态的分子和病理生物学分析人类 CRC 揭示 Kras* 驱动并维持侵袭性和转移性疾病，其中 Kras* 表达与骨髓源性抑制细胞 (MDSC) 的显着增加和骨髓源性抑制细胞 (MDSC) 的减少相关杀伤性T细胞。初步机制研究表明 Kras* 激活 TGFβ，进而抑制 IRF2（主要干扰素调节因子），导致干扰素反应受到抑制。干扰素网络通常发挥促进抗肿瘤反应的作用。因此，我们本研究的总体目标是评估两个假设：(1) Kras*/TGFβ 介导的 IRF2 抑制会产生免疫抑制性肿瘤促进癌症进展的微环境，以及 (2) Kras* 驱动的免疫抑制可能提供大多数 CRC 中观察到的对免疫检查点阻断 (ICB) 疗法的从头耐药性的基础患者。为了实现这些目标，我们提出以下具体目标：在目标 1 中，我们将描述利用我们的新型 CRC 小鼠模型，在原发性 CRC 中由 Kras* 驱动的免疫抑制细胞亚型，以及评估 Kras* 突变对 MDSC 和 TAM 活性的影响，以确定信号分子控制这些肿瘤的免疫抑制。在目标 2 中，我们将确定 TGFβ 的作用机制抑制 IRF2，并确定 Kras* 驱动的 CRC 中 IRF2 调节的免疫回路，这可能有助于免疫抑制肿瘤微环境促进癌症进展。在目标 3 中，我们将调查 CRC 中关键 Kras* 调控靶点的中和是否可以逆转免疫原发性耐药检查点阻断疗法。总的来说，该提案旨在确定新颖的组合以改善 Kras* CRC 中的 ICB 敏感性。