Project 172038

The fundamental action of vitamin D in the treatment and prevention of rickets was discovered over 60 years ago, but it is only recently that this compound was shown to have unique properties for treating cancer and osteoporosis. As vitamin D has no intrinsic activity, prior to its action it must be converted to 1,25-dihydroxyvitamin D (1,25(OH)2D), a powerful inhibitor of cell growth in many types of cells. However, many questions remain on how 1,25(OH)2D regulates these functions, and under which conditions and in which form(s) it should be administered. We have recently elucidated some fundamental questions on how 1,25(OH)2D acts at the cellular and molecular levels and we propose to translate these discoveries into broad applications in cancer and non-cancer states. First we discovered that phosphorylation of a central switch in the cell machinery, the retinoid X receptor (RXR), rendered the action of vitamin D ineffective in skin cancer cells, leading to a defect I called "relative vitamin D resistance in cancer cells". Our efforts are now focusing on how RXR phosphorylation perturbs the cellular machinery, and on devising strategies to reverse this phenomenon. We also discovered that cancer cells themselves could be used advantageously to treat cancer in a simple and effective way, with little side effects. Indeed, we have shown recently that inactive vitamin D can be metabolically activated within cancer cells and suppress cancer growth and metastasis to bone. Our next objective is to better understand this phenomenon by engineering mouse models in which the cells are unable to metabolize vitamin D into its active form. These models will be used to better understand the mechanism of action of vitamin D in skeletal metastasis prevention and treatment. Overall, our research program remains committed to better define the role of vitamin D in health and disease, and to generate unique therapies to treat cancer and other diseases.