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: 10437599
• 负责人: Laura Marie Sipe
• 金额: $ 1.08万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10437599
• 关键词: Acceleration; Acids; Address; Affect; Agonist; Anastomosis - action; Bile Acids; Bile fluid; Body Weight; Body Weight decreased; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Risk Factor; Breast Cancer Treatment; Cancer Survivor; Cell Proliferation; Cells; Clinical; Common bile duct structure; Data; Dependence; Dietary Intervention; Digestion; FDA approved; Female; Fibroblasts; Gallbladder; Goals; Growth; Human; Immune; Implant; In Vitro; Intervention; Lead; Ligation; Link; Malignant Neoplasms; Mediating; Mediator of activation protein; Mentors; Metabolic; Minority Women; Modeling; Molecular; Mus; Neoplasm Metastasis; Obese Mice; Obesity; Oncogenic; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Phosphotransferases; Pre-Clinical Model; Premenopause; Receptor Activation; Receptor Signaling; Recurrence; Relapse; Reporting; Retrospective Studies; Risk; Role; Secondary to; Signal Transduction; Testing; Therapeutic; Thinness; Time; Training; Transgenic Mice; Treatment Efficacy; Tumor Immunity; Tumor Suppression; Tumor Suppressor Proteins; Weight; aggressive breast cancer; bariatric surgery; breast cancer progression; cancer cell; cancer risk; cancer subtypes; clinically relevant; diet-induced obesity; high risk; ileum; improved; in vivo; innovation; loss of function; malignant breast neoplasm; metabolic profile; migration; molecular targeted therapies; mortality; mouse model; novel; novel therapeutics; pre-clinical; receptor; receptor expression; relapse prediction; sham surgery; targeted treatment; training opportunity; treatment response; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; tumor progression; young woman

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 acidFXRTNBC 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) 是一种侵袭性亚型，与肥胖相关，不成比例地 影响年轻和少数族裔女性；由于没有针对这种亚型的分子靶向治疗，结果仍然存在 肥胖会引起肿瘤微环境的免疫和代谢变化，从而导致更高的风险。 侵袭、转移和复发的风险，以及治疗反应不佳和死亡率较高。 尽管肥胖与乳腺癌之间存在已知的关联，但其机制上的相互依赖性仍不清楚。 接受减肥手术的患者患乳腺癌（包括 TNBC）的风险显着降低。 前提是与手术引起的减肥独特相关的潜在有益机制可以 因此，其最终目标是模仿手术的好处来降低癌症风险。 提议是测试新的药物治疗方法，以通过饮食和手术改善 TNBC 结局 手术减肥后的潜在益处是循环胆汁酸的高度升高。 胆汁酸受体法尼醇 X 受体 (FXR) 介导减肥和减肥的代谢益处 我们提供了关于 FXR 激活在减少体内 TNBC 进展中的作用的惊人初步数据。 免疫细胞的显着变化表明抗肿瘤免疫力得到改善。 在体外，我们发现激活可以抑制人和小鼠 TNBC 细胞的增殖、迁移和侵袭。 观察到 FXR 是 TNBC 无复发生存的重要预测因子，因此，我对此感到困惑。 通过减肥手术继发的胆汁酸升高或药物靶向 FXR 来激活 FXR，将 凭借我的培训和指导团队的专业知识，我已做好严格准备，以提高 TNBC 的成果。 研究潜在的胆汁酸FXRTNBC 机制以确定 FXR 激动剂的治疗效果。 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 - 使用创新的胆汁改道减肥手术相关的 TNBC 进展将确定是否有效。 使用 FDA 批准的现有 FXR 激动剂进行药理学 FXR 激活将提高治疗效果 TNBC。使用功能丧失模型目标 2 将确定 FXR 在肿瘤内在与外在中的贡献 减少 TNBC 的抗肿瘤免疫介导机制将产生重大影响。 第一个测试 TNBC 对胆汁酸和 FXR 的依赖性 对机制联系的了解有限。 乳腺癌和肥胖之间的关系构成了帮助患者的根本障碍，因为肥胖率是 上升，该项目的完成将最终解决 TNBC 治疗中未满足的迫切临床需求 提供特殊的 F32 训练机会。