Genetics and Biology of Metastatic Colorectal Cancer
Genetics and Biology of Metastatic Colorectal Cancer
批准号:
9768989
负责人:
RONALD ANTHONY DEPINHO
金额:
$35.38万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-09-01 至 2023-08-31
关键词:
AllelesAntitumor ResponseAutomobile DrivingBiologyCCR5 geneCXCL3 geneCancer EtiologyCatalogingCatalogsCellsCessation of lifeColon CarcinomaColorectal CancerCombined Modality TherapyCytometryCytotoxic T-LymphocytesDataDependenceDiseaseDown-RegulationDoxycyclineDrug CombinationsEngineeringGenesGeneticGenetic EpistasisGenomicsGoalsHumanIL8RB geneImmuneImmune TargetingImmunophenotypingImmunosuppressionInterferon SuppressionInterferonsKRAS2 geneMalignant neoplasm of prostateMediatingMicrosatellite RepeatsModelingMusMutationMyeloid-derived suppressor cellsNeoplasm MetastasisOncogenicPathway interactionsPatternPopulationProtein p53RANTESRepressionResistanceRoleSignal PathwaySignaling MoleculeTestingTherapeutic EffectTransforming Growth Factor betaTreatment EfficacyTumor-infiltrating immune cellsUnited StatesWomanWorkadenomaadvanced diseaseanti-PD-1basecancer cellcancer genomicschemokinechemokine receptorcolon cancer patientscolon cancer treatmentcolorectal cancer progressionhuman modelimmune checkpoint blockadeimmunoregulationimprovedinhibitor/antagonistmenmetastatic colorectalmolecular arraymortalitymouse modelnovelpreclinical trialprognosticrecruitresponsetargeted agenttrial designtumortumor microenvironmenttumor progression
中文摘要
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。
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Identifying and targeting collateral lethal vulnerabilities in cancers
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批准号:10563469
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项目类别:
-
资助金额:$96.7万
-
财政年份:2023
-
负责人:RONALD ANTHONY DEPINHO
-
依托单位:
Exploring Collateral Lethality for Development of Cancer Therapeutics
-
批准号:10365970
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项目类别:
-
资助金额:$46.43万
-
财政年份:2018
-
负责人:RONALD ANTHONY DEPINHO
-
依托单位:
Exploring Collateral Lethality for Development of Cancer Therapeutics
-
批准号:9899100
-
项目类别:
-
资助金额:$47.41万
-
财政年份:2018
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负责人:RONALD ANTHONY DEPINHO
-
依托单位:
Genetics and Biology of Metastatic Colorectal Cancer
-
批准号:10229510
-
项目类别:
-
资助金额:$36.48万
-
财政年份:2018
-
负责人:RONALD ANTHONY DEPINHO
-
依托单位:
Genetics and Biology of Metastatic Colorectal Cancer
-
批准号:10474624
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项目类别:
-
资助金额:$38.18万
-
财政年份:2018
-
负责人:RONALD ANTHONY DEPINHO
-
依托单位:
Cancer Clinical Investigator Team Leadership Award
-
批准号:8759976
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项目类别:
-
资助金额:$5.0万
-
财政年份:2013
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负责人:RONALD ANTHONY DEPINHO
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依托单位:
Cancer Center Support Grant - CTRP Supplement
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批准号:8759942
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项目类别:
-
资助金额:$7.5万
-
财政年份:2013
-
负责人:RONALD ANTHONY DEPINHO
-
依托单位:
Program Leaders of Research Programs
-
批准号:8759762
-
项目类别:
-
资助金额:$57.04万
-
财政年份:2013
-
负责人:RONALD ANTHONY DEPINHO
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依托单位:
Genetic Engineering Mouse Core
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批准号:8052127
-
项目类别:
-
资助金额:$8.38万
-
财政年份:2011
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负责人:RONALD ANTHONY DEPINHO
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依托单位:
FUNCTIONAL GENOMIC IDENTIFICATION AND CHARACTERIZATION OF THERAPEUTIC TARGETS
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批准号:8052103
-
项目类别:
-
资助金额:$31.95万
-
财政年份:2011
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负责人:RONALD ANTHONY DEPINHO
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依托单位:
ADMINISTRATION CORE
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批准号:8052128
-
项目类别:
-
资助金额:$3.43万
-
财政年份:2011
-
负责人:RONALD ANTHONY DEPINHO
-
依托单位:
The role of FOXO transcriptional factors in TSC-mediated tumorigenesis
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批准号:7679614
-
项目类别:
-
资助金额:$20.52万
-
财政年份:2008
-
负责人:RONALD ANTHONY DEPINHO
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依托单位:
The role of FOXO transcriptional factors in TSC-mediated tumorigenesis
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批准号:7511002
-
项目类别:
-
资助金额:$17.1万
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财政年份:2008
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负责人:RONALD ANTHONY DEPINHO
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依托单位:
Project 1: Targeting Metabolic Dependencies in PDAC
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批准号:9074440
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项目类别:
-
资助金额:$57.52万
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财政年份:2006
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负责人:RONALD ANTHONY DEPINHO
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依托单位:
Genetics and Biology of Pancreatic Duct Adenocarcinoma
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批准号:7591831
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项目类别:
-
资助金额:$183.84万
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财政年份:2006
-
负责人:RONALD ANTHONY DEPINHO
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依托单位:
Genetics and Biology of Pancreatic Ductal Adenocarcinoma
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批准号:8019210
-
项目类别:
-
资助金额:$201.96万
-
财政年份:2006
-
负责人:RONALD ANTHONY DEPINHO
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依托单位:
Genetics and Biology of Pancreatic Ductal Adenocarcinoma
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批准号:8603762
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项目类别:
-
资助金额:$205.71万
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财政年份:2006
-
负责人:RONALD ANTHONY DEPINHO
-
依托单位:
Genetics and Biology of Pancreatic Duct Adenocarcinoma
-
批准号:7223402
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项目类别:
-
资助金额:$177.09万
-
财政年份:2006
-
负责人:RONALD ANTHONY DEPINHO
-
依托单位:
Genetics and Biology of Pancreatic Duct Adenocarcinoma
-
批准号:7754684
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项目类别:
-
资助金额:$189.92万
-
财政年份:2006
-
负责人:RONALD ANTHONY DEPINHO
-
依托单位:
Genetics and Biology of Pancreatic Duct Adenocarcinoma
-
批准号:7928430
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项目类别:
-
资助金额:$48.8万
-
财政年份:2006
-
负责人:RONALD ANTHONY DEPINHO
-
依托单位:
海外基金