Exploiting the Tumor Microenvironment to Block Breast Cancer Bone Metastasis

描述（由申请人提供）：TGFß在骨微环境中的肿瘤效应被认为驱动乳腺癌的溶解性骨转移（B-MET）。然而，所有现有的骨特异性治疗药物都作用于肿瘤细胞的下游，抑制破骨细胞活性和骨吸收，这些药物已证明在B-MET治疗而非预防方面有效。我们最近从姜黄中分离出含姜黄素的提取物，发现姜黄素可以抑制实验性乳腺癌B- MET和阻断肿瘤细胞TGFß信号传导。我们的核心假设是，当在辅助治疗中单独使用或与标准破骨细胞靶向药物（双膦酸盐、denosumab）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肿瘤细胞TGFß信号传导，将有助于乳腺癌B-MET化学预防。除了这种预防乳腺癌B-MET的创新方法之外，研究人员还提出了一种新的药代动力学模式，假设姜黄多酚类姜黄素的糖醛酸化代谢物，在人体中很容易检测到，作为前药，在骨肿瘤微环境中选择性激活（去糖醛酸化和氧化），形成氧化代谢物，降低肿瘤细胞对TGFß的反应性。利用多种tgf ß-反应细胞系和体内B-MET模型，Specific Aim 1将确定体内骨转移部位姜黄素去糖醛酸化和氧化的药代动力学，以及骨和肿瘤细胞对姜黄素代谢的特异性体外影响。在Specific Aim 2中，姜黄素及其代谢产物调节与乳腺癌骨转移风险相关的“TGFß基因信号”的能力将被比较，它们在阻断肿瘤细胞TGFß信号传导方面的作用模式将被确定，使用这些相同的细胞系和体内模型。最后，在Specific Aim 3中，姜黄衍生的姜黄素膳食补充剂在单独使用或与双膦酸盐联合使用时提高乳腺癌骨转移预防治疗率的能力将通过三种独特的TGFß反应性乳腺癌骨转移模型进行测试，包括体内评估治疗对肿瘤细胞TGFß信号传导和骨吸收的影响。该研究项目的最终目标是为姜黄素在乳腺癌治疗中的应用建立一个新的范例，并可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.