As many as 20% of aggressive prostate cancers have mutations resulting in upregulation of Wnt/ß-catenin
signaling. Importantly, recent analysis identified the Wnt/ß-catenin pathway as the foremost differentially
modulated pathway among treatment-resistant individuals. We used structure-based design of peptidomimetic
oligomers to discover new molecules capable of inhibiting Wnt/ß-catenin signaling and prostate cancer cell
growth. We identified macrocycle 13 as a potent inhibitor of Wnt/ß-catenin signaling. In this proposal we outline
a strategy to use macrocycle 13 in models of castration resistant prostate cancer (CPRC) and to explore the
biology of Wnt/ß-catenin in prostate cancer. The hypothesis underlying of this project is that oligomer
macrocycles can be rationally designed to inhibit the ß-catenin/TCF interaction, thereby inhibiting prostate
cancer tumor growth. Our specific aims are to 1) test macrocycle 13 inhibition of ¿-catenin/TCF in in vivo
models of aggressive prostate cancer and 2) determine macrocycle 13/ß-catenin binding characteristics.
Altogether, we expect that completion of our research goals will provide new molecular insight into Wnt/ß-
catenin signaling in prostate cancer.