Grant: Travel Awards - Institute Community Support

Prostate cancer (PCa) initially responses to androgen ablation or castration, but progression to incurable castrate-resistant prostate cancer (CRPC) often occurs within three years. Androgen receptor pathway inhibitor Enzalutamide (ENZ) has produced promising survival gains of patients with CRPC. However, resistance to this novel therapy also rapidly occurs and novel treatment strategies are needed. We have recently developed a unique ENZ and castrate-resistant LNCaP xenograft model. To identify key regulators and active pathways in ENZ resistant cells, genome-wide gene expression analysis was performed and analyzed using systems biological approaches. We identified that forkhead box M1 (FOXM1) is one of the key upstream regulators activated in ENZ resistant PCa cells. FOXM1 is overexpressed in several cancers and it is an important regulator of cancer characteristics such as cell cycle, proliferation, invasion, metastases and cancer stem cells. Interestingly, our in silico gene expression analysis indicated that induced FOXM1 target gene signature significantly reduces disease free survival in prostate cancer patients. Moreover, FOXM1 signature was highly expressed in high Gleason score samples in silico. Furthermore, FOXM1 staining correlated with high Gleason score in our tissue microarray data. Using systems biological approaches, we further found out that the antibiotic ionophore and oxidative stress inducer Monensin that was previously identified as a cancer-specific PCa and a potential cancer stem cell inhibitor, reduces FOXM1 pathway activity in ENZ resistant cells. The in vitro validation results indicated that Monensin reduced cell viability, FOXM1 transcriptional activity as well as FOXM1 protein, gene and its target gene expressions in ENZ resistant PCa cells. Taken together, the results suggest that inhibition of FOXM1 by Monensin is a potent novel mean to target ENZ resistant prostate cancer.