Grant: Operating Grant

A lack of vitamin D has been linked to several types of cancer including breast cancer. In earlier studies we have shown that vitamin D blocks the production of another hormone called parathyroid hormone related protein or PTHrP. PTHrP is produced by the great majority of breast tumors and when overproduced accelerates the development of bone metastases. Based on these observations we believe that we can target this vitamin D-PTHrP axis to counter the development of bone metastases. The majority of breast cancer patients who have a recurrence will develop cancer spread to the skeleton, which causes considerable suffering and morbidity. Bone metastases are currently treated with bisphosphonates that inhibit osteoclast bone lytic activity. Unfortunately, bisphosphonate treatment is not a cure and the number of patients experiencing skeletal complications is reduced by only 20%, which exemplifies the need for improving the efficacy of bisphosphonate therapy. Recent evidence points to the existence in tumors of a small population of multi-potent therapy-resistant cancer stem cells (CSC) that survive treatment to regenerate tumors locally and produce metastases. One aspect of this proposal is to examine the possibility of countering breast cancer metastatic spread to the skeleton by targeting of the CSC population through the vitamin D-PTHrP axis. We believe that the combination of vitamin D therapy, specific blockade of PTHrP activity, and bisphosphonate treatment in a co-targeting strategy will create an enhanced treatment addressing all levels of metastatic spread from breast to the skeleton. Another aspect of this proposal is to improve the efficacy of vitamin D by targeting specific signaling molecules that render the cancer cells resistant to the effect of vitamin D. Overall our goal is to develop pre-clinical models of vitamin D-based therapies. If successful, these strategies will constitute proofs of principle for therapeutic intervention.