Alex Pham

Introduction: Castration resistant prostate cancer is a progression of prostate cancer that results when cancer cells develop mechanisms that enable them to stimulate their own androgen receptors.¹ It is estimated about 10-20% of prostate cancers will progress to CRPC and the estimated mean survival of CRPC patients is between 9 to 36 months.² Right now, the gold standard of care for prostate cancer is androgen deprivation therapy.³ The resumed expression of multiple androgen receptor-regulated genes in CRPC allows continued tumor growth and survival thus rendering androgen deprivation therapy useless.¹ The main treatment for CRPC patients is Enzalutamide which competitively inhibits androgens and prevents them from binding to the androgen receptor in cancer cells.⁴ However, over time resistance has become prevalent to it and therefore has greatly diminished its therapeutic efficacy. Wnt//b-catenin signaling pathway elicits target genes that promote androgen independent growth which renders the mechanism of Enzalutamide ineffective. Methods: First, MR49F and C4-2R prostate cancer cells with elevated Wnt/b-catenin levels and Enzalutamide resistance were treated with ICG001 (Wnt/b-catenin pathway inhibitor) and/or Enzalutamide to determine efficacy of combined treatment. Second, mice carrying Enzalutamide-resistant prostate cancer received Enzalutamide, ICG001, or combined therapy for 3 weeks. Third, prostate cancer stem cells were treated with an inhibitor or activator of the Wnt/b-catenin pathway (capsaicin or LiCl respectively). Results: Cell viability and colony formation showed a greater decrease in cancer cell growth with combination therapy of Enzalutamide and ICG001 compared to Enzalutamide or the inhibitor alone.¹ Tumor volume after Enzalutamide treatment alone showed no statistical difference from control group due to conferred resistance, while combination treatment resulted in a synergistic decrease of tumor volume.¹ Consistently, inhibition of Wnt/b-catenin pathway leads to lower viability of prostate cancer stem cells compared to prostate cancer stem cells with an active Wnt/b-catenin pathway.⁸  Conclusions: Activation of the Wnt/b-catenin pathway in Enzalutamide sensitive cells leads to drug resistance, whereas b-catenin inhibitor resensitized resistant prostate cancer cells to the therapeutic effects of Enzalutamide.

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