Therapeutic Role of Bmi-1 Inhibitors in Eliminating Prostate Tumor Stem Cells

Prostate tumor-initiating cells (TICs) have intrinsic resistance to current therapies. BMI-1 (B-cell-specific MMLV insertion site-1) regulates stem cell self-renewal, and is over-expressed in TICs. We developed a combined immunophenotypic and time-ofadherence assay to identify human prostate TICs with increased BMI-1 expression. Tumor initiation and dissemination were consistently observed in the immune-permissive zebrafish microenvironment from collagen-adherent 2 1hi/CD44hi cells. Utilizing the zebrafish xenograft model, we identified the first known translational inhibitors of BMI-1 that target prostate TICs. BMI-1 inhibitors induced prostate cancer cell senescence, and G1 cell cycle arrest. Targeting of BMI-1 significantly reduced clonogenic, migration, and invasion abilities of TICs, and increased cellular senescence. Treatment of zebrafish and mouse xenografts with BMI-1 inhibitor reduced the metastatic potential of zebrafish TIC-derived xenografts, and inhibited tumor growth in mouse xenografts, respectively. Therefore, we have accomplished our first year s goal to demonstrate the beneficial effects of targeting prostate TICs with BMI-1 inhibitors. The next phase of studies will examine BMI-1 targeted therapy in combination with Taxotere and other recently approved therapies. These studies will allow us to accomplish the goals of this synergistic award between three laboratories (Sabaawy, Bertino, and Kim) to develop a therapeutic strategy for BMI-1 inhibitors in prostate cancer.
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