Exploiting the Tumor Microenvironment to Block Breast Cancer Bone Metastasis

描述（由申请方提供）：认为骨微环境中TGF β的肿瘤效应可驱动乳腺癌中的溶解性骨转移（B-MET）。然而，所有现有的骨特异性治疗剂（已证明在B-MET治疗中有效，但在预防中无效）均作用于肿瘤细胞下游，抑制破骨细胞活性和骨吸收。我们最近有了新的发现，从姜黄中分离的含姜黄素的提取物，一种来自古代植物治疗学的丰富药典的药物，抑制实验性乳腺癌B- MET并阻断肿瘤细胞TGF β信号传导。我们的核心假设是，当单独使用或与标准破骨细胞靶向药物（双磷酸盐、狄诺塞单抗）联合使用时，含有姜黄素的姜黄膳食补充剂阻断骨微环境中的肿瘤细胞TGF β信号传导将有助于乳腺癌B-MET化学预防。设置。除了这种预防乳腺癌B-MET的创新方法之外，一旦临床上明显，这种方法就无法治愈，研究人员还提出了一种新的药代动力学范式，认为姜黄多酚类姜黄素的II期葡萄糖醛酸代谢物，在人体中很容易检测到，作为前药，在骨肿瘤微环境中，TGF β 1和TGF β 2在骨肿瘤微环境中相互作用（去葡萄糖醛酸化和氧化）以形成降低肿瘤细胞对TGF β 1的反应性的氧化代谢物。使用多种TGF β-应答细胞系和体内B-MET模型，特异性目标1将确定体内骨转移部位姜黄素类化合物脱葡萄糖醛酸化和氧化的药物动力学，以及骨和肿瘤细胞对姜黄素类化合物代谢的特异性体外作用。在具体目标2中，将比较姜黄素及其代谢产物调节与乳腺癌骨转移风险相关的“TGF β基因特征”的能力，并将使用这些相同的细胞系和体内模型确定其阻断肿瘤细胞TGF β信号传导的作用模式。最后，在具体目标3中，将使用三种独特的TGF β-响应性乳腺癌骨转移模型测试姜黄衍生的姜黄素类膳食补充剂在单独使用或与双膦酸盐组合使用时改善乳腺癌骨转移预防的治疗比率的能力，包括对肿瘤细胞TGF β信号传导和骨细胞骨吸收的治疗效果的体内评估。该研究项目的最终目标是建立一个新的模式，用于姜黄素在乳腺癌的管理，可以在未来的临床试验中进行测试。

DESCRIPTION (provided by applicant): Tumor effects of TGFß in the bone microenvironment are thought to drive lytic bone metastases (B-MET) in breast cancer. However, all existing bone-specific therapeutics, which have demonstrated efficacy in B-MET treatment but not prevention, act downstream of tumor cells, inhibiting osteoclast activity and bone resorption. We have recently made the novel discovery that curcuminoid-containing extracts isolated from turmeric, a medicinal from the rich pharmacopeia of ancient botanical therapeutics, inhibit experimental breast cancer B- MET and block tumor cell TGFß signaling. Our core hypothesis is that blockade of tumor cell TGFß signaling in the bone microenvironment by curcuminoid-containing turmeric dietary supplements will aid in breast cancer B-MET chemoprevention when used in isolation or combination with standard osteoclast-targeted agents (bisphosphonates, denosumab) in the adjuvant setting. In addition to this innovative approach to prevention of breast cancer B-MET, which are incurable once clinically evident, the investigators also advance a novel pharmacokinetic paradigm, positing that that phase II, glucuronidated metabolites of turmeric's polyphenolic curcuminoids, which are readily detectable in humans, act as pro-drugs that are selectively activated (deglucuronidated and oxidized) within the bone tumor microenvironment to form oxidative metabolites that decrease tumor cell responsiveness to TGFß. Using multiple TGFß-responsive cell lines and in vivo B-MET models, Specific Aim 1 will determine the pharmcokinetics of curcuminoid deglucuronidation and oxidization in vivo at sites of bone metastases as well as the specific in vitro effects of bone and tumor cells on curcuminoid metabolism. In Specific Aim 2, the ability of curcuminoids and their metabolites to modulate the "TGFß gene signature" associated with breast cancer bone metastases risk will be compared and their mode of action in blocking tumor cell TGFß signaling will be determined using these same cell lines and in vivo models. Lastly, in Specific Aim 3, the ability of turmeric-derived curcuminoid dietary supplements to improve the therapeutic ratio for breast cancer bone metastases prevention when used in isolation or in combination with bisphosphonates will be tested using three unique TGFß-responsive breast cancer bone metastases models, including in vivo assessments of treatment effects on tumor cell TGFß signaling and osteoclastic bone resorption. The ultimate goal of this research project is to establish a new paradigm for curcuminoid use in the management of breast cancer that can be tested in future clinical trials.