UC Davis

The next-generation antiandrogen drugs such as enzalutamide and abiraterone extend survival times and improve the quality of life in patients with advanced prostate cancer. However, resistance to antiandrogens occurs frequently through mechanisms that are incompletely understood. Wnt signaling, particularly through Wnt5a, plays vital role in promoting prostate cancer progression and induction of resistance to enzalutamide and abiraterone. My research has focused on understanding the potential role of the Wnt5a/FZD2-mediated non-canonical Wnt pathway in enzalutamide-resistant prostate cancer. My study has found that Wnt5a and FZD2 are upregulated upon the development of enzalutamide resistance and that their overexpression correlates with higher Gleason score, biochemical recurrence and metastatic status, and with shortened disease-free survival duration. Importantly, blocking the Wnt5a/FZD2 signal transduction not only diminished the activation of non-canonical Wnt signaling but also suppressed the expression and function of constitutively activated androgen receptor (AR) and AR variants. Furthermore, we developed a novel bioengineered BERA-Wnt5a siRNA construct and demonstrated that inhibition of Wnt5a expression by the BERA-Wnt5a siRNA significantly suppressed tumor growth and enhanced enzalutamide treatment in vivo. These results indicate that Wnt5a/FZD2 signal pathway plays a critical role in promoting enzalutamide resistance and that targeting this pathway by BERA-Wnt5a siRNA can be developed as a potential therapy to treat advanced prostate cancer.Treatment-emergent neuroendocrine prostate cancer often occurs after AR-tarted therapies. Thus, my research further investigated the emergence of neural lineage features in enzalutamide-resistant prostate cancer. Ninety-five-gene signature of neural lineage (NLS) was identified from C4-2B MDVR and neuroendocrine prostate cancer patient databases. These NLS genes positively correlate with conventional NE markers such as chromogranin and synaptophysin and negatively correlate with PSA, AR and AR target genes in NEPC compared to prostate adenocarcinoma. These differentially expressed NLS genes stratify small-cell neuroendocrine prostate cancer from prostate adenocarcinoma. The expression of ARHGEF2, LHX2, and EPHB2 among the 95 NLS genes correlates with shortened survival time by Kaplan-Meier analysis. Further studies demonstrated that ARHGEF2 suppression could serve as a potential therapeutic strategy to prevent early neuroendocrine differentiation in enzalutamide-resistant prostate cancer.