rTS Signaling Mimetics As Novel Cancer Therapeutics

DESCRIPTION (provided by applicant): The Dolnick laboratory recently reported a novel signaling pathway governing both the level of thymidylate synthase protein (TS) and the cytoskeleton function in human cancer cells. This pathway plays an important role in determining cell proliferation and sensitivity to at least two major classes of anticancer drugs (i.e., antifolates and antimicrotubules). Dr. Dolnick and his collaborators have since identified an agent (3-oxododecanoyl homoserine lactone, or 3-oxo-C12-HSL, or OHL) that acts through this pathway and enhances the activity of TS inhibitors, in H630 human colorectal cancer cells. The utility of this agent, however, is limited by its high lipophilicity and poor aqueous solubility. The present application is to develop a suitable OHL formulation designed to produce maximal antitumor activity and to evaluate in vivo activity of OHL as single agent and in combination with 5-fluorouracil. The proposed studies represent collaboration between scientists with diverse expertise important in successful cancer therapy development, i.e., discovery of novel molecular targets, pharmacokinetics and pharmacodynamics (PK and PD), drug delivery to solid tumors, and translational sciences (in vitro- to-in vivo and preclinical-to-clinical). The specific aims are: (1) develop OHL-loaded nano-sized delivery systems with different drug release characteristics, and (2) to evaluate activity of the selected OHL- loaded formulation in tumor-bearing mice.