Accession Number : ADA624243


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


Descriptive Note : Annual rept. 30 Sep 2014-29 Sep 2015


Corporate Author : RUTGERS - THE STATE UNIV NEW BRUNSWICK NJ


Personal Author(s) : Bertino, Joseph ; Sabaawy, Hatem E ; Kim, Isaac


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a624243.pdf


Report Date : Oct 2015


Pagination or Media Count : 89


Abstract : 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.


Descriptors :   *NEOPLASMS , *PROSTATE CANCER , *PROTEINS , *STEM CELLS , ASSAYING , DRUGS , INHIBITORS , MICE , TISSUES(BIOLOGY)


Subject Categories : Biochemistry
      Anatomy and Physiology
      Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE