The role of bile acids to ameliorate obesity driven triple negative breast cancer

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，这样做的最终目标 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），介导的减肥和代谢的好处， 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。对机械联系的有限理解 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。

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.