MUC1-C Oncoprotein Evades Immune Destruction in Non-small Cell Lung Cancer
MUC1-C 癌蛋白在非小细胞肺癌中逃避免疫破坏
基本信息
- 批准号:9913473
- 负责人:
- 金额:$ 62.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-04-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdenocarcinomaAntibodiesAntibody-drug conjugatesBedsBiopsyC-terminalCancer EtiologyCancer PatientCancer cell lineCell physiologyCellsCessation of lifeCytoplasmic TailDevelopmentDiseaseEpidermal Growth Factor ReceptorExtracellular DomainGene ExpressionGenetically Engineered MouseGlycoproteinsGrantHumanImmuneImmune EvasionImmune signalingImmunocompetentImmunotherapeutic agentIn VitroInfiltrationInflammationInvestigationKRAS2 geneLinkMalignant NeoplasmsMalignant neoplasm of lungMonoclonal AntibodiesMucin 1 proteinMucinsMutationN-terminalNon-Small-Cell Lung CarcinomaOncogenicOncoproteinsPD-1 blockadePD-1/PD-L1PD-L1 blockadePDL1 pathwayPathogenesisPathway interactionsPatientsPhenotypePlayPolymersPrimary NeoplasmProductionProteinsReceptor ActivationReceptor SignalingResearchResectedRoleShapesSignal PathwaySignal TransductionSpecimenT-LymphocyteTherapeutic AgentsTumor-associated macrophagesTumorigenicityUnited StatesWorkbasecancer cellcancer genomicscancer therapycytokineeffective therapyextracellulargene therapyimmune checkpointimprovedinhibitor/antagonistmacrophagemutantnanoparticlenovelnovel strategiesoutcome forecastoverexpressionprogrammed cell death ligand 1recruitresponseself-renewaltargeted agenttargeted treatmenttherapeutic targettreatment strategytumortumor microenvironmenttumor xenograft
项目摘要
Non-small cell lung cancers (NSCLCs), particularly those with activating KRAS mutations, are often
unresponsive to targeted agents and have a poor prognosis. However, immunotherapeutic approaches,
particularly PD-1/PD-L1 pathway blockade, have recently improved the treatment of these cancers, supporting
the premise that evasion of immune destruction contributes to NSCLC pathogenesis. MUC1-C is an
oncogenic protein that is overexpressed in >80% of NSCLCs and is linked to multiple immune signaling
pathways.
Work supported by this grant has demonstrated that EGFR mutant NSCLCs activate the PD-1/PD-L1 pathway
and increase production of proinflammatory cytokines. We have also shown that MUC1-C promotes (i)
oncogenic signaling in NSCLCs via EGFR activation, and (ii) confers EMT, self-renewal and tumorigenicity in
KRAS mutant NSCLCs. Based on these findings, we have generated novel antibodies against the non-shed
MUC1-C extracellular domain and inhibitors of the cytoplasmic domain for therapeutic targeting of MUC1-C in
NSCLC cells.
Our preliminary observations indicate that targeting MUC1-C downregulates PD-L1 expression in EGFR and
KRAS mutant NSCLC cells. We have also found that MUC1-C deficiency is associated with recruitment of
tumor-associated macrophages and alterations in the infiltrating T-cell phenotype. Our hypothesis is that
MUC1-C plays an important role in evading immune destruction, which will be addressed in studies of (i)
human NSCLC cell lines, (ii) genetically engineered mouse models, and (iii) primary NSCLC tumors.
The Specific Aims are: (1) To investigate the role of MUC1-C in PD-L1 pathway activation in EGFR and KRAS
mutant NSCLC cells, (2) To define the role of MUC1-C in recruitment and function of macrophages and T-cells
within the tumor microenvironment of KRAS and EGFR mutant NSCLC, (3) To evaluate the effects of targeting
MUC1-C to circumvent immune evasion in mutant EGFR and KRAS NSCL tumors, and (4) To assess fresh
resected/biopsied lung cancer specimens and correlate MUC1 expression with T-cell and other immune cell
infiltration, immune checkpoint gene expression, and cytokine secretion in the tumor microenvironment.
非小细胞肺癌(nsclc),特别是那些激活KRAS突变的肺癌
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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DONALD W. KUFE其他文献
DONALD W. KUFE的其他文献
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{{ truncateString('DONALD W. KUFE', 18)}}的其他基金
Targeting MUC1-C with an antibody drug conjugate for the therapy of advanced prostate cancer
使用抗体药物偶联物靶向 MUC1-C 治疗晚期前列腺癌
- 批准号:
10512804 - 财政年份:2022
- 资助金额:
$ 62.43万 - 项目类别:
Targeting MUC1-C for the Treatment of Small Cell Lung Cancer Progression
靶向 MUC1-C 治疗小细胞肺癌进展
- 批准号:
10354347 - 财政年份:2022
- 资助金额:
$ 62.43万 - 项目类别:
Targeting MUC1-C for the Treatment of Small Cell Lung Cancer Progression
靶向 MUC1-C 治疗小细胞肺癌进展
- 批准号:
10563188 - 财政年份:2022
- 资助金额:
$ 62.43万 - 项目类别:
MUC1-C is a Target for Reversing Immune Evasion and Resistance to Immunotherapies
MUC1-C 是逆转免疫逃避和免疫疗法耐药性的靶点
- 批准号:
9789217 - 财政年份:2018
- 资助金额:
$ 62.43万 - 项目类别:
MUC1-C is a Target for Reversing Immune Evasion and Resistance to Immunotherapies
MUC1-C 是逆转免疫逃避和免疫疗法耐药性的靶点
- 批准号:
10004595 - 财政年份:2018
- 资助金额:
$ 62.43万 - 项目类别:
MUC1-C is a Target for Reversing Immune Evasion and Resistance to Immunotherapies
MUC1-C 是逆转免疫逃避和免疫疗法耐药性的靶点
- 批准号:
10478059 - 财政年份:2018
- 资助金额:
$ 62.43万 - 项目类别:
MUC1-C is a Target for Reversing Immune Evasion and Resistance to Immunotherapies
MUC1-C 是逆转免疫逃避和免疫疗法耐药性的靶点
- 批准号:
10224740 - 财政年份:2018
- 资助金额:
$ 62.43万 - 项目类别:
MUC1-C Oncoprotein Evades Immune Destruction in Non-small Cell Lung Cancer
MUC1-C 癌蛋白在非小细胞肺癌中逃避免疫破坏
- 批准号:
9238148 - 财政年份:2012
- 资助金额:
$ 62.43万 - 项目类别:
Functional role of the MUC1-C oncoprotein in non-small cell lung cancer
MUC1-C 癌蛋白在非小细胞肺癌中的功能作用
- 批准号:
8837576 - 财政年份:2012
- 资助金额:
$ 62.43万 - 项目类别:
Functional role of the MUC1-C oncoprotein in non-small cell lung cancer
MUC1-C 癌蛋白在非小细胞肺癌中的功能作用
- 批准号:
8634063 - 财政年份:2012
- 资助金额:
$ 62.43万 - 项目类别:
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