Grant: Project Grant

We have developed a novel class of molecules as potential cancer therapeutics that possess two distinct but complementary biochemical (or drug) activities within a single molecular backbone - essentially acting as two drugs in one. We previously found that molecules that mimic the action of vitamin D (VDR agonists) in combination with drugs (HDACi) that inhibit the activity of enzymes called histone deacetylases (HDACs) strongly cooperate to kill cancer cells. As individual drugs can be cleared by the body at different rates, complicating therapy with drug combinations, we sought to develop single molecules that act both as VDR agonists and as HDACi; i.e. functioning as two drugs in one. These "bifunctional" molecules represent a novel class of therapeutics. Our work over a number of years combining chemical synthesis with characterization of molecular function led to the production of series of molecules that acted as both VDR agonists and HDACi. Moreover, these molecules could be assembled in relatively few and simple steps of chemical synthesis. Our goals in this grant application are to understand in detail how our hybrid molecules produce their therapeutic effect and to further develop their potential in preclinical studies to identify molecules with the potential to be used as actual drugs. The work essentially entails three parts. (i) We will use cancer cells in culture to understand the molecular details of how the two drug activities combine to produce a therapeutic effect. (ii) We will produce new hybrid molecules with improved properties. (iii) We will study the therapeutic potential of our lead molecules in several mouse models of cancer for which there has been relatively little therapeutic advance in the last few years, including advanced squamous carcinoma of the head and neck and so-called "triple-negative" breast cancer.