Exploiting the Tumor Microenvironment to Block Breast Cancer Bone Metastasis

利用肿瘤微环境阻止乳腺癌骨转移

基本信息

批准号：
8759032
负责人：
JANET L FUNK
金额：
$ 32.35万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8759032
关键词：
Adjuvant Automobile Driving Beta-glucuronidase Biological Biological Availability Bone Matrix Bone Metastases Prevention Bone Resorption Bone neoplasms Botanicals Breast Cancer Cell Breast Cancer Prevention Cell Line Cells Chemoprevention Clinical Management Clinical Trials Development Dietary Supplementation Drug Kinetics Drug Targeting Female Future Genes Genetic Transcription Goals Health Human In Vitro Lytic Malignant Neoplasms Mammary Neoplasms Metabolic Biotransformation Metabolism Metastatic Neoplasm to the Bone Modeling Neoplasm Metastasis Osteoclasts Osteolytic PTGS2 gene Pathway interactions Pharmacopoeias Phase Population Prevention Prevention approach Process Prodrugs Research Research Personnel Research Project Grants Risk Role Safety Serum Signal Transduction Site Testing Therapeutic Translations Tumeric Woman advanced disease bisphosphonate bone bone cell cofactor cost dietary supplements drug discovery improved in vivo in vivo Model inhibitor/antagonist innovation interest malignant breast neoplasm neoplastic cell neutralizing antibody novel prevent receptor therapeutic target treatment effect tumor tumor microenvironment

项目摘要

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.

描述（由申请人提供）：骨微环境中的 TGFβ 的肿瘤作用被认为会导致乳腺癌中的溶解性骨转移 (B-MET)，然而，所有现有的骨特异性疗法均已证明在 B-MET 治疗中有效，但仍存在缺陷。不是预防，而是作用于肿瘤细胞的下游，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（一种来自姜黄的药物）中分离出含有姜黄素的提取物。丰富的古代植物疗法药典，抑制实验性乳腺癌 B-MET 并阻断肿瘤细胞 TGFβ 信号传导我们的核心假设是，含有类姜黄素的姜黄膳食补充剂阻断骨微环境中的肿瘤细胞 TGFβ 信号传导将有助于乳腺癌 B- 治疗。除了这种创新方法之外，MET 化学预防还可以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、狄诺塞麦）联合使用。为了预防乳腺癌 B-MET（一旦临床上证明 B-MET 是无法治愈的），研究人员还提出了一种新的药代动力学范式，假设姜黄多酚类姜黄素的 II 期葡萄糖醛酸化代谢物（在人体中很容易检测到）充当前药，在骨肿瘤微环境中被选择性激活（去葡萄糖醛酸化和氧化），形成氧化代谢物，降低肿瘤细胞对TGFß。使用多种 TGFß 反应细胞系和体内 B-MET 模型，具体目标 1 将确定骨转移部位体内姜黄素脱葡萄糖醛酸化和氧化的药代动力学，以及骨和肿瘤细胞对骨转移的体外具体影响。类姜黄素代谢。在具体目标 2 中，类姜黄素及其代谢物调节“TGFß”的能力。将比较与乳腺癌骨转移风险相关的“基因特征”，并使用这些相同的细胞系和体内模型确定它们阻断肿瘤细胞 TGFβ 信号传导的作用模式。最后，在具体目标 3 中，姜黄衍生的能力姜黄素膳食补充剂可提高乳腺癌骨转移预防的治疗率，该补充剂单独使用或与双磷酸盐联合使用时，将使用三种独特的 TGFβ 反应性乳腺癌骨转移进行测试该研究项目的最终目标是建立姜黄素在乳腺癌治疗中的应用新范例，并可在未来的临床试验中进行测试。