Grant: Project Grant

An estimated 35,000 people die from bone metastases each year in Canada, and skeletal complications before death cause considerable suffering and morbidity. Bone metastases are currently treated with anti-resorptive agents such as the potent bisphosphonate zoledronate or Denosumab (Xgeva). Unfortunately, this is not a cure and the number of patients experiencing skeletal complications is reduced by only 40% with no survival benefit, which exemplifies the need for improving the efficacy of such therapy. A lack of vitamin D has been linked to several types of cancer including breast cancer and the majority of breast cancer patients who have a recurrence will develop cancer spread to the skeleton. Active forms of vitamin D have anti-cancer properties but have not been effective when administered in humans. Significant side effects limit their use at high doses that can lead to hypercalcemia (elevation of blood calcium) with severe consequences such as tissue calcification and heart arrhythmias. Our goals are to understand how vitamin D may be beneficial to patients with bone metastasis, and to develop improved vitamin D therapies with minimal side effects by enhancing the local activity of vitamin D in the bone microenvironment to prevent its systemic effects and hypercalcemia-related complications. These novel therapies will be combined with currently approved anti-resorptive therapies such as bisphosphonates and Denosumab to treat/prevent bone metastasis in breast cancer patients. Overall, we propose to develop pre-clinical models that will serve as proofs of principle for therapeutic intervention in breast cancer spreading to the skeleton.