Exploiting the Tumor Microenvironment to Block Breast Cancer Bone Metastasis

描述(由申请人提供)：转化生长因子在骨微环境中的肿瘤效应被认为是乳腺癌中溶骨性骨转移(B-MET)的驱动因素。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，抑制破骨细胞的活性和骨吸收，这些药物在B-MET治疗中显示了有效性，但没有预防作用。我们最近有了一个新的发现，从姜黄中分离出含有姜黄素的提取物，这是一种从古代植物疗法的丰富药典中提取的药物，可以抑制实验性乳腺癌B-MET，并阻断肿瘤细胞的转化生长因子？信号。我们的核心假设是，含有姜黄素的膳食补充剂通过阻断骨骼微环境中的肿瘤细胞TGFb信号将有助于乳腺癌的B-MET化学预防，当单独使用或与标准破骨细胞靶向药物(双磷酸盐、迪诺单抗)在佐剂环境中联合使用时。除了这种预防乳腺癌B-MET的创新方法(一旦临床证明是无法治愈的)，研究人员还提出了一种新的药代动力学范例，假设在人类中很容易检测到的姜黄多酚姜黄素的II相葡萄糖糖醛酸化代谢产物作为前体药物，在骨肿瘤微环境中被选择性地激活(去葡萄糖醛酸化和氧化)，形成氧化代谢产物，从而降低肿瘤细胞对转化生长因子的反应。利用多种转化生长因子反应细胞系和体内的B-MET模型，特异性目标1将确定姜黄素在体内骨转移部位的脱葡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体外特异性影响。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“转化生长因子基因信号”的能力，并将使用这些相同的细胞系和体内模型来确定它们在阻断肿瘤细胞转化生长因子？信号方面的作用模式。最后，在具体目标3中，姜黄源姜黄素膳食补充剂单独使用或与双膦酸类药物联合使用时，将使用三种独特的转化生长因子-反应乳腺癌骨转移模型来测试其提高乳腺癌骨转移预防的治疗率的能力，包括对肿瘤细胞转化生长因子？信号转导和破骨细胞性骨吸收的治疗效果的体内评估。这项研究项目的最终目标是建立一种新的姜黄素用于乳腺癌治疗的范例，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 TGFb 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.