Therapeutic Role of Bmi-1 Inhibitors in Eliminating Prostate Tumor Stem Cells
Annual rept. 30 Sep 2013-29 Sep 2014
RUTGERS - THE STATE UNIV NEW BRUNSWICK NJ
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Current prostate cancer PCa management calls for identifying novel and more effective therapeutic approaches. Self-renewing prostate tumor-initiating cells TICs hold intrinsic therapy-resistance and account for tumor relapse and progression. BMI-1 Bcell- specific MMLV insertion site-1 regulates stem cell self-renewal, thus, impairing BMI-1 function for TICs-tailored therapies appears to be a promising approach. During the first year of this award, we developed a combined immunophenotypic and time-of- adherence assay to identify CD49bhiCD29hiCD44hi cells as TICs from prostatectomy tissues Kim Lab. We have also identified the first known translational inhibitors of BMI-1 that target prostate TICs. Employment of a specific BMI-1 inhibitor on patient-derived cells significantly decreased spheroid formation in vitro and prevented tumor initiation in vivo in mice Bertino Lab, thereby diminishing the frequency of TICs. Furthermore, BMI-1 inhibitors induced prostate cancer cell senescence, and G1 cell cycle arrest. BMI-1 inhibition, while displaying antitumor activity in zebrafish xenografts Sabaawy lab, did not exert toxic effects on normal tissues. BMI-1 targeted therapy when combined with taxotere resulted in further antitumor activities. These data offer a paradigm for targeting TICs for a more effective PCa treatment. Therefore, we have accomplished our second year s goal to demonstrate the beneficial effects of targeting prostate TICs in vivo with BMI-1 inhibitors in 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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