Estrogen receptors restrict tumor-promoting inflammation in K-ras mutant lung cancer
雌激素受体限制 K-ras 突变肺癌中促肿瘤的炎症
基本信息
- 批准号:10386921
- 负责人:
- 金额:$ 3.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:Bone Marrow TransplantationCancer EtiologyCellsCessation of lifeClinical TrialsDNA Sequence AlterationDevelopmentEpithelialEstrogen Receptor alphaEstrogen Receptor betaEstrogen ReceptorsEstrogensFemaleGenesGeneticGenotypeGoalsGonadal Steroid HormonesImmuneImmunotherapyInfiltrationInflammationInflammatoryInterleukin-6KRAS2 geneKnock-outLightLungLung NeoplasmsMalignant NeoplasmsMalignant neoplasm of lungMeasuresMediatingModalityModelingMusMutant Strains MiceMutateMutationMyelogenousMyeloid CellsNuclear Hormone ReceptorsOutcomePathway interactionsPatientsPhenotypePlayProductionProtein IsoformsRattusReceptor GeneReceptor SignalingRiskRoleSTAT3 geneSignal TransductionSmokerStructure of parenchyma of lungSystemTestingTumor BurdenTumor ImmunityTumor-infiltrating immune cellsUnited StatesViral Oncogenebasecancer clinical trialcancer typecarcinogenesiscell typecigarette smokedriver mutationdruggable targetfemale sex hormoneindividualized medicineinhibitorinterestmalemenmutantneoplastic cellnovel therapeuticspersonalized medicinepromoterreceptor bindingrecruitresistance mechanismresistance mutationsarcomasexsex disparitysingle-cell RNA sequencingtargeted treatmenttranscription factortumortumor microenvironmenttumorigenesis
项目摘要
Abstract
More patients die from lung cancer than from any other cancer type each year in the United States. Moreover,
lung cancers with K-ras driver mutations are resistant to targeted therapies. Therefore, there is an unmet need
to find druggable targets downstream of K-ras. Tumor-promoting inflammation occurs frequently as a result of
K-ras mutations that activate the NF-κB pathway, the production of interleukin 6, and activation of its downstream
transcription factor STAT3. However, when we knock out STAT3 in tumor cells in mice, females have fewer
tumors, but males have more. This sex disparity is driven by overactivation of NF-κB in males, but in females,
estrogen signaling reduces NF-κB and tumor-promoting inflammation. This protective phenotype requires
estrogen receptors (ERs), nuclear hormone receptors that bind estrogen and interact with NF-κB. There are two
genes for ERs: ERα and ERβ. ERβ is the major ER isoform expressed in lung tissue, and ERα is mainly in
immune cells. Accordingly, I hypothesize that in the absence of STAT3 in the lung epithelium, ERα and ERβ
signaling is protective in K-ras mutant lung cancer by inhibiting NF-κB-driven pro-tumor inflammation. I have two
specific aims to test this hypothesis, one aim for each of the cellular compartments of interest: tumor cells and
myeloid cells. Aim 1: I will knock out ERβ in tumors to determine if it is required for cancer protection in females.
Aim 2: since ERα predominates in tumor-infiltrating myeloid immune cells, I will knock out ERα in myeloid cells
to determine if it is also required for cancer protection. Successful completion of these aims will further explain
the mechanism of ER-dependent lung cancer protection, with potential for estrogen and ERα/ERβ to play a novel
therapeutic role. Since clinical trials for STAT3 inhibitors have begun, it is important to understand the sex-
specific outcomes of targeting STAT3. Our results will guide clinicians to better personalize therapy by taking
sex hormones into account when treating patients. They will also shed light on the mechanism of resistance to
currently available immunotherapies and provide alternative modalities.
摘要
项目成果
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Michael Joseph Clowers其他文献
Michael Joseph Clowers的其他文献
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{{ truncateString('Michael Joseph Clowers', 18)}}的其他基金
Estrogen receptors restrict tumor-promoting inflammation in K-ras mutant lung cancer
雌激素受体限制 K-ras 突变肺癌中促肿瘤的炎症
- 批准号:
10583464 - 财政年份:2022
- 资助金额:
$ 3.42万 - 项目类别:
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