Therapeutic Role of Bmi-1 Inhibitors in Eliminating Prostate Tumor Stem Cells
Annual rept. 30 Sep 2014-29 Sep 2015
RUTGERS - THE STATE UNIV NEW BRUNSWICK NJ
Pagination or Media Count:
Current prostate cancer PCa management calls for identifying novel and more effective therapeutic approaches that could target therapy resistant self-renewing prostate tumor-initiating cells TICs. Our focus is on BMI-1 B-cell-specific MMLV insertion site-1, a protein that regulates stem cell self-renewal. During the first two years of this award and in collaboration with the initiating and other partnering PIs, we have developed and optimized a time-of-adherence assay to identify TICs that we demonstrated to have CD49bhiCD29hiCD44hi cell phenotype. This year, we examined the first known translational inhibitors of BMI-1 C-209 to target prostate TICs alone and in combination with taxotere, the standard of care. Employment of this 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 from a large number of patients tissues. Furthermore, C-209 induced cell senescence, G1 cell cycle arrest, and reduced intratumor BMI-1 levels, while displaying antitumor activity in mouse xenografts did not exert toxic effects on normal tissues. BMI-1 targeted therapy when combined with taxotere resulted in further antitumor activities. Therefore, we have accomplished our third year s goal to demonstrate the beneficial effects of targeting prostate TICs in vivo in mice in this synergistic award between three laboratories Sabaawy, Bertino, and Kim to develop a therapeutic strategy for BMI-1 inhibitors in prostate cancer.
- Anatomy and Physiology
- Medicine and Medical Research