Role of microbial-modulated bile acid receptor signaling in breast cancer
微生物调节胆汁酸受体信号传导在乳腺癌中的作用
基本信息
- 批准号:10053592
- 负责人:
- 金额:$ 41.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:7alpha hydroxylaseAblationAddressAdjuvantAffectAggressive behaviorAgonistAntibioticsBile AcidsBlood CirculationBody Weight decreasedBreastBreast Cancer CellBreast Cancer ModelBreast Cancer PatientCell CommunicationCellsClinicalDataDietary InterventionEnterohepatic CirculationEstrogen ReceptorsGenerationsGeneticGoalsGrowthHumanHydroxylationImmuneImmune checkpoint inhibitorImmunologic SurveillanceImmunosuppressionImmunotherapeutic agentImmunotherapyImplantIn VitroIncidenceIntestinal NeoplasmsIntestinesKnowledgeLinkLiverMalignant NeoplasmsMammary NeoplasmsMammary glandMediatingMediator of activation proteinMetabolicMicrobeModelingModificationMusNeoplasm MetastasisObesityOutcomePathologicPathway interactionsPatient-Focused OutcomesPatientsPharmacologyPhysiologicalPlayPrimary carcinoma of the liver cellsRaceReceptor SignalingRelapseReportingRoleSamplingSecondary toShapesSignal TransductionStromal CellsTestingTherapeuticTimeTissuesTreatment EfficacyTumor ImmunityTumor MarkersTumor SubtypeTumor stageWeightWorkbacterial metabolismbariatric surgerybreast cancer progressioncancer cellcancer immunotherapycancer subtypescarcinogenicitychemotherapycommensal microbesexperimental studyfecal transplantationgain of functiongut microbiomegut microbiotahost microbiotaimprovedinnovationmalignant breast neoplasmmicrobialmicrobial communitymicrobiomemicrobiome alterationmicrobiome researchmicrobiotamigrationmimeticsnonhuman primatenovelnovel therapeuticspersonalized medicineprecision medicinereceptorreceptor expressionresponsesmall moleculetargeted treatmenttherapeutic evaluationtriple-negative invasive breast carcinomatumortumor microenvironmenttumor progressiontumor-immune system interactions
项目摘要
SUMMARY
Anti-tumor immunity varies due to interactions between innate and adaptive immune cells, microbial
community diversity, host and microbially derived metabolites, and other local factors that shape tumoricidal
responses. While most of the recent microbiome research focuses on the gut microbiome and cancer
outcomes, extra-intestinal microbial communities are detected in the tumor microenvironment (TME). We
recently reported that specific microbes identified in patient breast tumors compared to pathologically normal
breast samples associated with tumor stage, tumor subtype, and for the first time, race. Triple Negative Breast
Cancer (TNBC), an aggressive subtype that has generally eluded personalized medicine approaches,
contained unique microbes that may mediate immunosuppression and impact standard chemotherapy or
immune checkpoint inhibitor (ICI) efficacies. Yet to date, mechanisms underpinning these observations are
unresolved as to how the gut and/or extra-intestinal microbiome influence BC onset, progression, and
response to therapies, which is a major knowledge gap in this field. One cogent mechanism that may link
microbes to anti-tumor immunity are microbially modified metabolites, namely bile acids. Certain microbes rich
in 7-alpha-hydroxylase convert primary to secondary bile acids which regulate bile acid composition. Bile acids
have been shown to limit progression and metastasis in other cancers through reversing immunosuppression,
but minimal work has explored the role of bile acids in BC. Bile acids signal through several bile acid receptors
including farnesoid X receptor (FXR). We posit that specific gut or local resident microbes that impact bile acid
pools and composition will interact with cells expressing FXR to regulate the TME immune milieu. We report for
the first time that patients with high FXR expression have greater relapse-free survival uniquely in TNBC
subtype, but not in less aggressive luminal BC subtype, suggesting potential for targeted approaches. The
overall objective of this proposal is to test mechanisms linking MicrobesBile AcidsTNBC which poses an
opportunity to generate novel therapeutics and precision medicine informed by microbial compositions. Our
innovative approach interrogates targetable microbial pathways that we demonstrate change the microbiome,
bile acids, and tumor progression. Our central hypothesis is microbial composition and microbially-modified
metabolic products, such as bile acids, increase immunotherapeutic efficacy through reprogramming the TME
leading to enhanced anti-tumor immunity. We will test our hypothesis by performing the following aims: 1)
Determine if commensal microbes play a physiological role in TNBC anti-tumor immunity; 2) Determine if the
microbiome alters immunosurveillance of early tumor onset and progression; 3) Determine if pharmacologic
bile acid receptor agonism improves TNBC immunotherapy. Findings generated will have high impact because
the lack of targeted therapies for TNBC presents a great unmet clinical need and could be transformative to
improve patient outcomes.
总结
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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Liza Makowski-Hayes其他文献
Liza Makowski-Hayes的其他文献
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{{ truncateString('Liza Makowski-Hayes', 18)}}的其他基金
Determining susceptibility loci in triple negative breast cancer using a novel pre-clinical model
使用新型临床前模型确定三阴性乳腺癌的易感位点
- 批准号:
10573287 - 财政年份:2022
- 资助金额:
$ 41.73万 - 项目类别:
Determining the contribution of microbial-derived metabolites to protective immunity in obesity-driven cancer risk.
确定微生物衍生的代谢物对肥胖驱动的癌症风险中的保护性免疫的贡献。
- 批准号:
10505372 - 财政年份:2022
- 资助金额:
$ 41.73万 - 项目类别:
Determining susceptibility loci in triple negative breast cancer using a novel pre-clinical model
使用新型临床前模型确定三阴性乳腺癌的易感位点
- 批准号:
10444546 - 财政年份:2022
- 资助金额:
$ 41.73万 - 项目类别:
Role of microbial-modulated bile acid receptor signaling in breast cancer
微生物调节胆汁酸受体信号传导在乳腺癌中的作用
- 批准号:
10404525 - 财政年份:2020
- 资助金额:
$ 41.73万 - 项目类别:
Role of microbial-modulated bile acid receptor signaling in breast cancer
微生物调节胆汁酸受体信号传导在乳腺癌中的作用
- 批准号:
10219210 - 财政年份:2020
- 资助金额:
$ 41.73万 - 项目类别:
Role of microbial-modulated bile acid receptor signaling in breast cancer
微生物调节胆汁酸受体信号传导在乳腺癌中的作用
- 批准号:
10614037 - 财政年份:2020
- 资助金额:
$ 41.73万 - 项目类别:
(PQA2) Reversing Carcinogenic Effect of Obesity on Basal-like Breast Cancer
(PQA2) 逆转肥胖对基底样乳腺癌的致癌作用
- 批准号:
8590946 - 财政年份:2013
- 资助金额:
$ 41.73万 - 项目类别:
Macrophage Mitochondrial Stress in Inflammation, Insulin Resistance & Obesity
炎症、胰岛素抵抗中的巨噬细胞线粒体应激
- 批准号:
8208231 - 财政年份:2007
- 资助金额:
$ 41.73万 - 项目类别:
Macrophage Mitochondrial Stress in Inflammation, Insulin Resistance & Obesity
炎症、胰岛素抵抗中的巨噬细胞线粒体应激
- 批准号:
8121191 - 财政年份:2007
- 资助金额:
$ 41.73万 - 项目类别:
Macrophage Mitochondrial Stress in Inflammation, Insulin Resistance & Obesity
炎症、胰岛素抵抗中的巨噬细胞线粒体应激
- 批准号:
7479191 - 财政年份:2007
- 资助金额:
$ 41.73万 - 项目类别:
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