Identification of drugs that increase cisplatin uptake by inhibiting CTR2
CTR2 has shown to be a particularly attractive target against which to develop a drug that both inhibits tumor growth and sensitizes to platinum drugs. In this project, Dr. Howell will establish a robust assay to evaluate the function of CTR2 that can be used to identify molecules that can serve as the starting point for subsequent structure-activity studies and refinement of structure to produce a lead compound for pre-clinical testing. Dr. Howell’s group feels that this can be achieved by first screening to find molecules that enhance cisplatin toxicity, then conducting a secondary screen that directly measure the cellular uptake of cisplatin and its interaction with DNA. The specific aims are to 1) establish a primary assay that detects a CTR2-specific increase in the toxicity of a low concentration of cisplatin and 2) establish a series of secondary screens that quantify the CTR2-dependent cellular accumulation of cisplatin and its ability to damage DNA.