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：
10229510
负责人：
RONALD ANTHONY DEPINHO
金额：
$ 36.48万
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/10229510
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 human model immune checkpoint blockade immunoregulation improved inhibitor/antagonist men metastatic colorectal molecular array mortality mouse model novel preclinical trial prognostic recruit response targeted agent therapeutically effective 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/摘要该提案旨在剖析其在控制CRC免疫方面的致癌KRAS（KRAS*）的作用生物学的目的是阐明有效的CRC患者测试治疗策略。一系列在我们的小鼠模型中比较了kras*`'''''''''''''''''''''''''kras*'kras和病理学分析。人CRC透露，KRAS*与Kras*一起驱动并保持侵入性和转移性疾病。表达与髓样衍生的抑制细胞（MDSC）显着增加并减少杀手T细胞。初步机械研究表明，KRAS*激活TGFβ，这又代表 IRF2（主干扰素调节因子），导致干扰素反应抑制。干扰素网络通常功能以促进抗肿瘤反应。那就是我们在这项研究中的总体目标是评估两个假设：（1）KRAS*/TGFβ介导的IRF2表示会产生免疫抑制肿瘤微环境实现癌症的进展，（2）KRAS*驱动的免疫抑制可能会提供在大多数CRC中观察到的对免疫检查点封锁（ICB）治疗的抗性基础的基础患者。为了实现这些目标，我们提出以下具体目标：在AIM 1中，我们将表征利用我们的新型CRC小鼠模型在主要CRC中驱动的Kras*驱动的免疫抑制细胞亚型，并且评估KRAS*突变对MDSC和TAM活性的影响以识别信号分子这些肿瘤中的免疫抑制。在AIM 2中，我们将确定TGFβ的机制抑制IRF2，并识别IRF2在KRAS*驱动的CRC中调节的免疫电路进行免疫抑制性肿瘤微环境，实现癌症的进展。在AIM 3中，我们将调查 CRC中关键KRAS*调节靶标的中和是否可以逆转对免疫的一级抗性检查点封锁治疗。总的来说，该建议旨在确定新颖的组合以改善 KRAS* CRC中的ICB灵敏度。