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SPORE Project 2

Project 2 - Treatment of PDAC with Wnt/β-catenin Inhibitors
                   Donald J. Buchsbaum, Ph.D. (UAB) - Basic Co-Leader
                   Mansoor Saleh, M.D. (UAB) - Clinical Co-Leader
                   Mark Suto, Ph.D. (SR) - Co-Investigator
                   Yonghe Li, Ph.D. (UAB) - Co-Investigator
                   Patsy Oliver, Ph.D. (UAB) - Co-Investigator

Project 2 will determine whether novel Wnt/β-catenin inhibitors with high specificity for pancreatic tumor cells and cancer initiating cells will circumvent chemoresistance and exhibit efficacy against PDAC. The UAB CCC-Southern Research Consortium facilitated the synthesis of novel benzimidazole compounds at Southern Research, and testing at UAB revealed that these compounds are more water-soluble than the previously identified Wnt/β-catenin inhibitor niclosamide; inhibit Wnt/β-catenin signaling in PDAC cell lines; and produce greater cytotoxicity to cancer initiating cells than to bulk tumor cells. Aim 1 will identify a primary and a back-up compound that inhibit Wnt/β-catenin signaling and are suitable for IND-enabling studies for the treatment of PDAC. Aim 2 will define the mechanism of action for these compounds in combination with current chemotherapies in PDAC xenograft models. Aim 3 will examine the effect of the benzimidazole compounds on the Wnt/β-catenin pathway and chemoresistance. Finally, preclinical IND-enabling safety studies will be completed in Aim 4 to identify a benzimidazole compound suitable for IND filing and a phase I clinical trial.

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