Abstract 4279: Targeting Bmi1 in human prostate tumor initiating cells
Authors: Bansal Nitu , Campbell Neil , Medina Daniel , DiPaola Robert , Bertino Joseph R. , Sabaawy Hatem E. 
Published: February 2011

Prostate cancer stem cells or tumor initiating cells (TICs) represent a barrier to effective treatment due to their intrinsic resistance to current therapeutic modalities. Recent studies identified Bmi-1 (B-cell specific MMLV insertion site-1), a member of the polycomb family of chromatin remodeling complexes, as a major oncogenic protein that is highly expressed in, and regulates stem cells and prostate TIC self-renewal. We found that shRNA specific targeting or pharmacological inhibition of the critical stem cell and TIC protein Bmi-1 in cultured prostate tumors resulted in cell death. These studies were extended to demonstrate that Bmi-1 plays an equally critical role in prostate TIC maintenance in patient tumors, and that targeting Bmi-1 eliminates the subpopulation of TICs resistant to hormone ablation and currently used chemotherapies. We utilized a novel zebrafish xenograft of primary human prostate tumor model to identify candidate Bmi-1 inhibitory drugs and other drugs targeting TIC pathways for further preclinical and clinical testing. First, we isolated and characterized TICs from fresh human prostate tissues from patients undergoing resection, and then utilized the zebrafish primary xenograft model to evaluate TIC growth, and to define Bmi-1 and other stem cell associated pathways as bonafide TIC targets. Next, we investigated Bmi-1 and other TIC inhibitors in enriched prostate stem cells and the zebrafish model, and the results were confirmed in the mouse xenograft model to determine efficacy and toxicity. Zebrafish bearing Du145 xenografts were compared to fish bearing fresh human TICs, and the combinations of Bmi-1 inhibitor(s) with taxotere, a drug approved for use in the treatment of advanced prostate cancer were synergistic. Our studies are extended to determine the features of prostate TICs in zebrafish xenograft assays, and to study the effects of Bmi-1 inhibitors in sensitized microenvironments lacking the downstream targets P16INK4a and p19Arf, in order to analyze the changes in Bmi-1 targets regulating survival, proliferation, and cancer stem cell maintenance. The novel aspects of these studies are the growth inhibition of human prostate TICs, and the use of zebrafish as an in vivo model to determine Bmi-1 inhibitor efficacy, doses and combinations with conventional therapies. Bmi-1 inhibitors that target prostate cancer TICs may provide a new class of potent inhibitors that when used alone and in combination with other targeted therapy would represent an effective therapeutic management for patients with prostate cancer. Moreover, the use of zebrafish would allow the rapid generation of response to therapy data that would facilitate the development of drugs targeted to prostate TICs.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4279.