Abstract
Purpose: Current prostate cancer management calls for identifying novel and more effective therapies. Self-renewing tumor-initiating cells (TICs) hold intrinsic therapy resistance and account for tumor relapse and progression. As BMI-1 regulates stem cell self-renewal, impairing BMI-1 function for TIC-tailored therapies appears to be a promising approach. Experimental Design: We have previously developed a combined immunophenotypic and time-of-adherence assay to identify CD49bhiCD29hiCD44hi cells as human prostate TICs. We utilized this assay with patient-derived prostate cancer cells and xenograft models to characterize the effects of pharmacologic inhibitors of BMI-1. Results: We demonstrate that in cell lines and patient-derived TICs, BMI-1 expression is upregulated and associated with stem cell-like traits. From a screened library, we identified a number of post-transcriptional small molecules that target BMI-1 in prostate TICs. Pharmacologic inhibition of BMI-1 in patient-derived cells significantly decreased colony formation in vitro and attenuated tumor initiation in vivo, thereby functionally diminishing the frequency of TICs, particularly in cells resistant to proliferation- and androgen receptor-directed therapies, without toxic effects on normal tissues. Conclusions: Our data offer a paradigm for targeting TICs and support the development of BMI-1-targeting therapy for a more effective prostate cancer treatment.
| Original language | English |
|---|---|
| Pages (from-to) | 6176-6191 |
| Number of pages | 16 |
| Journal | Clinical Cancer Research |
| Volume | 22 |
| Issue number | 24 |
| DOIs | |
| State | Published - Dec 15 2016 |
Bibliographical note
Publisher Copyright:©2016 AACR.
Funding
We thank Drs. Maarten van Lohuizen (The Netherlands Cancer Institute) for the BMI-1 knockout mouse embryonic fibroblasts (MEFs), and Leonard Zon (Harvard University, Cambridge, MA) for the Casper zebrafish. We thank Dr. David Augeri and members of his laboratory at the Department of Chemistry at Rutgers University for the synthesis and purification of the small molecules utilized in this study. This project was supported by the Department of Defense Grant (W81XWH-12-1-0249 to H.E. Sabaawy), National Cancer Institute (P30 CA072720; to R.S. DiPaola), the New Jersey Commission on Cancer Research (NJCCR) Grant (09-1137-CCR-EO to H.E. Sabaawy), Rutgers Cancer Institute of New Jersey (pilot grant to J. Bertino and H.E. Sabaawy), Wellcome Trust grant (SDDI award # 092687; to PTC Therapeutics) and New Jersey Health Foundation award (research grant; to H.E. Sabaawy). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
| Funders | Funder number |
|---|---|
| Leonard Zon | |
| Netherlands Cancer Institute | |
| New Jersey Commission on Cancer Research | 09-1137-CCR-EO |
| U.S. Department of Defense | W81XWH-12-1-0249 |
| U.S. Department of Defense | |
| National Childhood Cancer Registry – National Cancer Institute | P30CA072720 |
| National Childhood Cancer Registry – National Cancer Institute | |
| New Jersey Health Foundation | |
| Harvard Transdisciplinary Research in Energetics and Cancer Center, Harvard University | |
| Rutgers Cancer Institute of New Jersey and Rutgers University | |
| Wellcome Trust | 092687 |
| Wellcome Trust |
ASJC Scopus subject areas
- General Medicine
