The role of bile acids to ameliorate obesity driven triple negative breast cancer
胆汁酸在改善肥胖引起的三阴性乳腺癌中的作用
基本信息
- 批准号:10437599
- 负责人:
- 金额:$ 1.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-04 至 2022-08-15
- 项目状态:已结题
- 来源:
- 关键词:AccelerationAcidsAddressAffectAgonistAnastomosis - actionBile AcidsBile fluidBody WeightBody Weight decreasedBreast Cancer CellBreast Cancer ModelBreast Cancer Risk FactorBreast Cancer TreatmentCancer SurvivorCell ProliferationCellsClinicalCommon bile duct structureDataDependenceDietary InterventionDigestionFDA approvedFemaleFibroblastsGallbladderGoalsGrowthHumanImmuneImplantIn VitroInterventionLeadLigationLinkMalignant NeoplasmsMediatingMediator of activation proteinMentorsMetabolicMinority WomenModelingMolecularMusNeoplasm MetastasisObese MiceObesityOncogenicOperative Surgical ProceduresOutcomePathway interactionsPatientsPharmaceutical PreparationsPharmacological TreatmentPharmacologyPhosphotransferasesPre-Clinical ModelPremenopauseReceptor ActivationReceptor SignalingRecurrenceRelapseReportingRetrospective StudiesRiskRoleSecondary toSignal TransductionTestingTherapeuticThinnessTimeTrainingTransgenic MiceTreatment EfficacyTumor ImmunityTumor SuppressionTumor Suppressor ProteinsWeightaggressive breast cancerbariatric surgerybreast cancer progressioncancer cellcancer riskcancer subtypesclinically relevantdiet-induced obesityhigh riskileumimprovedin vivoinnovationloss of functionmalignant breast neoplasmmetabolic profilemigrationmolecular targeted therapiesmortalitymouse modelnovelnovel therapeuticspre-clinicalreceptorreceptor expressionrelapse predictionsham surgerytargeted treatmenttraining opportunitytreatment responsetriple-negative invasive breast carcinomatumortumor microenvironmenttumor progressionyoung woman
项目摘要
Triple negative breast cancer (TNBC) is an aggressive subtype, associated with obesity, that disproportionately
affects young and minority women; with no molecularly targeted therapies for this subtype, outcomes remain
very poor. Obesity induces immune and metabolic changes to the tumor microenvironment that lead to higher
risk of invasion, metastases, and recurrence, as well as poor response to therapy and higher mortality. Despite
known associations, the mechanistic interdependencies between obesity and breast cancer remain unclear.
Patients who underwent bariatric surgery had significantly reduced risk of breast cancer, including TNBC. My
premise is that underlying beneficial mechanisms uniquely associated with surgically induced weight loss can
be capitalized upon to mimic the benefits of surgery to reduce cancer risk. Therefore, the ultimate goal of this
proposal is to test novel pharmacologic treatments to improve TNBC outcomes informed by diet and surgical
interventions. A potential mediator of benefits after surgical weight loss is highly elevated circulating bile acids.
The bile acid receptor, farnesoid X receptor (FXR), mediated weight loss and metabolic benefits of bariatric
surgery. We present striking preliminary data for a role of FXR activation in reducing TNBC progression in vivo
with significant changes in immune cells suggesting improved anti-tumor immunity. We also demonstrate FXR
activation blunts proliferation, migration and invasion in human and murine TNBC cells in vitro. In patients, we
observed that FXR is a significant predictor of relapse-free survival in TNBC. Therefore, I hypothesize that
activating FXR, via elevated bile acids secondary to bariatric surgery or pharmacologically targeting FXR, will
improve TNBC outcomes. With my training and expertise of my mentoring team, I am well poised to rigorously
investigate underlying bile acidFXRTNBC mechanisms to determine therapeutic efficacy of FXR agonism.
Aim 1 will use a preclinical TNBC model to determine to what extent elevated bile acids abrogate obesity-
associated TNBC progression using an innovative bile diversion bariatric surgery. Aim 2 will determine if
pharmacologic FXR activation using an existing FDA-approved FXR agonist will improve therapeutic efficacy for
TNBC. Using loss of function models Aim 2 will determine the contribution of FXR in tumor intrinsic vs. extrinsic
anti-tumor immune-mediated mechanisms to reduce TNBC. Outcomes from this proposal will be high impact as
the first to test the dependence of TNBC on bile acids and FXR. A limited understanding of the mechanistic links
between breast cancer and obesity pose a fundamental obstacle to helping patients. Since obesity rates are
rising, completion of this project will ultimately address an urgent unmet clinical need in TNBC treatment as well
as provide an exceptional F32 training opportunity.
三阴性乳腺癌(TNBC)是一种与肥胖相关的侵袭性亚型,
影响年轻和少数民族妇女;没有针对这种亚型的分子靶向治疗,
很穷。肥胖会诱导肿瘤微环境的免疫和代谢变化,导致肿瘤微环境中的高表达。
侵袭、转移和复发的风险,以及对治疗的不良反应和较高的死亡率。尽管
尽管肥胖与乳腺癌之间存在已知的联系,但其相互依赖的机制仍不清楚。
接受减肥手术的患者患乳腺癌的风险显著降低,包括TNBC。我
前提是,与手术诱导的体重减轻独特相关的潜在有益机制可以
可以利用来模仿手术的好处,以降低癌症风险。因此,最终的目标是
一项提案是测试新的药理学治疗方法,以改善饮食和手术告知的TNBC结果。
干预措施。手术减肥后获益的一个潜在介质是循环胆汁酸的高度升高。
胆汁酸受体,法尼醇X受体(FXR),介导的减肥和减肥药的代谢益处
手术我们提供了FXR激活在体内减少TNBC进展中的作用的惊人的初步数据
免疫细胞的显著变化表明抗肿瘤免疫力提高。我们还展示了FXR
体外活化减弱人和鼠TNBC细胞的增殖、迁移和侵袭。在患者中,我们
观察到FXR是TNBC无复发生存期的重要预测因子。因此,我假设
通过继发于减肥手术的胆汁酸升高或靶向FXR的胆汁酸升高激活FXR,
改善TNBC结果。凭借我的培训和我的指导团队的专业知识,我已经准备好严格地
研究潜在的胆汁酸-FXR-TNBC机制以确定FXR激动的治疗功效。
目标1将使用临床前TNBC模型来确定升高的胆汁酸在多大程度上消除肥胖-
相关的TNBC进展,使用创新的胆汁分流减肥手术。目标2将确定是否
使用现有FDA批准的FXR激动剂的药理学FXR激活将改善治疗效果,
TNBC。使用功能丧失模型,目标2将确定FXR在肿瘤内源性与外源性中的贡献
减少TNBC的抗肿瘤免疫介导机制。该提案的结果将产生很大影响,
第一个测试TNBC对胆汁酸和FXR的依赖性。对机械联系的理解有限
乳腺癌和肥胖症之间的联系是帮助病人的根本障碍。由于肥胖率是
该项目的完成也将最终解决TNBC治疗中迫切的未满足的临床需求
提供了一个特殊的F32训练机会。
项目成果
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Laura Marie Sipe其他文献
Laura Marie Sipe的其他文献
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{{ truncateString('Laura Marie Sipe', 18)}}的其他基金
The role of bile acids to ameliorate obesity driven triple negative breast cancer
胆汁酸在改善肥胖引起的三阴性乳腺癌中的作用
- 批准号:
10154863 - 财政年份:2021
- 资助金额:
$ 1.08万 - 项目类别:
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