THERAPEUTIC ROLE OF BMI-1 INHIBITORS IN ELIMINATING PROSTATE TUMOR STEM CELLS

Background: Prostate tumor-initiating cells (TICs) have the exclusive abilities to self-renew and to initiate tumors in immune-deficient recipients. Prostate TICs survive treatment due to their intrinsic resistance to current therapies. Elevated expression of Bmi-1 (B-cell specific MMLV insertion site) occurs in prostate tumor stem cells. Bmi-1 promotes tumorigenesis by repressing genes regulating cell cycle and apoptosis and by suppressing growth inhibitor proteins. Thus, Bmi-1 is an ideal drug target to eliminate self-renewal of prostate TICs. Pressing questions are whether Bmi-1 inhibitors are effective against prostate cancer and if combining Bmi-1 inhibitors with chemotherapy causes tumor eradication.Objective/Hypothesis: Our goal is to identify and subsequently develop a new class of bioavailable small molecules that inhibit tumor growth by selectively reducing Bmi-1 production. In preliminary studies, we found Bmi-1 to be overexpressed in 44% of advanced prostate tumors. We hypothesize that Bmi-1 plays a vital role in prostate TIC maintenance and that drugs targeting Bmi-1 will eliminate TICs in patient tumors. We have identified three potent and selective compounds that reduce Bmi-1 expression in prostate cancer cell lines in vitro and in vivo. We propose to use mice and zebrafish xenografts of primary cells to (1) select a compound(s) that potently, selectively, and safely reduce Bmi-1 expression in primary prostate TICs and (2) develop a clinical strategy for combination therapy.Specific Aims: (1) Determine the extent of aberrant expression of Bmi-1 in primary prostate tumors and study of the role of Bmi-1 in regulating prostate TIC self-renewal. (a) Analyses of Bmi-1 expression in primary and metastatic prostate cancer patients. (b) Study of the effects of Bmi-1 knockdown on putative TICs in vitro and in vivo with serially engrafted zebrafish and mice xenografts. (2) Evaluate the therapeutic response to combining small molecule Bmi-1 inhibitors with chemotherapy to eradicate prostate TIC xenografts. We have identified three Bmi-1 inhibitors with antitumor activity at ED50 of