Tumor effects of TGF 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 TGF signaling. Our core hypothesis is that blockade of tumor cell TGF 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 TGF. Using multiple TGF-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 "TGF gene signature" associated with breast cancer bone metastases risk will be compared and their mode of action in blocking tumor cell TGF 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 TGF-responsive breast cancer bone metastases models, including in vivo assessments of treatment effects on tumor cell TGF 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.
Women with breast cancer, the most common female cancer, are frequent users of botanical dietary supplements. Thus, the identification of a botanical product with proven efficacy (and lack of harm) when used in isolation or combination with standard therapeutics to prevent bone metastases, which are incurable and occur in the majority of women with advanced disease, could have a significant and timely effect on the clinical management of breast cancer. While TGFb responsiveness is known to enhance the invasive potential of breast cancer cells in bone, current therapeutics targeting this pathway are lacking. Development of evidence that novel oxidative metabolites of turmeric-derived curcuminoids act specifically to inhibit secretion of TGF-stimulated osteolytic factors by breast cancer cells would provide a novel rationale for curcuminoids use in metastatic breast cancer prevention and provide new leads for drug discovery. Lastly, while curcuminoids are of great oncologic interest in many cancers, enthusiasm for their use has been limited by the low bioavailability of unmetabolized curcuminoids. Elucidation of a role for the tumor microenvironment in the biotransformation of curcuminoids to form active metabolites with specific anti-tumor biological activities could propel curcuminoid oncologic research in an entirely new direction.