Enzalutamide and abiraterone are initially effective for the treatment of castration-resistant prostate cancer
(CRPC). However, resistance to both drugs occurs frequently through mechanisms which are incompletely
understood. Evidence from both clinical and experimental studies demonstrate that Wnt signaling, particularly
through Wnt5A, plays vital roles in promoting CRPC progression and induction of resistance to enzalutamide
and abiraterone. Development of novel strategies targeting Wnt5A to overcome resistance is an urgent need.
Preliminary and clinical data demonstrate that Wnt5A signaling is significantly activated in resistant CRPC cells
and specimens from CRPC patients. Down regulation of Wnt5A inhibits AR/AR variants expression, suppresses
cell growth, and resensitizes resistant cells to anti-androgen treatment. The objective of this proposal is to fully
delineate the role of Wnt5A signaling in drug resistance and determine the efficacy of targeting Wnt5A using two
novel strategies to overcome resistance. In Aim 1, we will determine the role of Wnt5A in the development of
resistance to enzalutamide and abiraterone. In aim 2, we will evaluate the efficacy of two novel strategies
targeting Wnt5A for inhibiting resistant CRPC tumor growth and re-sensitization to enzalutamide/abiraterone
treatment. In aim 3, we will elucidate the mechanisms of action by Wnt5A inhibition in resistant CRPC. We hope
that by completion of this study we will provide a novel therapeutic approach to treat advanced CRPC through
targeting Wnt5A. We also expect that targeting Wnt5A in conjunction with enzalutamide/abiraterone therapy will
increase the magnitude and duration of the benefits of second-generation antiandrogens.