Project 172278

The hormonal form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D) binds to the vitamin D receptor (VDR) and is a key regulator of calcium homeostasis. However, data from multiple sources, including one of the applicants (White), showed that 1,25D is a potent regulator of cell proliferation and differentiation, and has anticancer properties. Moreover, it is also a regulator of immune system function. Vitamin D insufficiency has been linked to elevated rates of various cancers, as well as autoimmune and infectious diseases. Therapeutic potential of 1,25D is limited by its tendency to raise calcium concentrations in blood (hypercalcemia). Moreover, cancer progression is associated with acquired resistance to 1,25D. However, resistance can be overcome in vitro by coadministration of the histone deacetylase (HDAC) inhibitor trichostatin A (TSA). HDAC inhibitors (HDACi) have emerged as a new class of therapeutic agents for treatment of cancer and other indications. However, a drawback of current HDACi's is their lack of specificity; e.g. HDACi's TSA and SAHA inhibit all 12 class I and II HDACs. We observed a synergistic effect of TSA and 1,25D on proliferation of 1,25D-resistant squamous carcinoma cells, and others demonstrated a combinatory effect in prostate and breast cancer. Based on these findings we designed a series of molecular hybrids that combine VDR agonism with HDAC inhibition incorporated into the molecules' side chains. Bifunctional compounds represent a powerful alternative to combination therapy. The best characterized hybrid, triciferol, combines VDR agonism with HDAC inhibition at nM concentrations, and, importantly, does not induce hypercalcemia. It was also more efficacious than 1,25D in in vitro cancer models. Unlike TSA or SAHA, the hybrids exhibit a range of HDAC specificities. To enhance the commercial potential of our hybrids, we must (i) define their HDAC specificity, and (ii) provide evidence of efficacy in vivo.