Exploiting the Tumor Microenvironment to Block Breast Cancer Bone Metastasis

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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.