DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

BMI-1 Targeting Eliminates Prostate Tumor Stem Cells

Posted December 28, 2016
Hatem Sabaawy, M.D. Ph.D.; Rutgers Cancer Institute of New Jersey
Joseph Bertino, M.D.; Rutgers Cancer Institute of New Jersey
Isaac Kim, M.D, Ph.D.; Rutgers Cancer Institute of New Jersey

Dr. Hatem Sabaawy
Dr. Hatem Sabaawy.
Photo provided by Rutgers Cancer Institute of New Jersey.

Dr. Joseph Bertino
Dr. Joseph Bertino.
Photo provided by Rutgers Cancer Institute of New Jersey.

Dr. Isaac Kim
Dr. Isaac Kim.
Photo provided by Rutgers Cancer Institute of New Jersey.

Treatment resistance and tumor relapse are frequent events in advanced prostate cancer (PCa) and novel, more effective therapeutics are greatly needed. Self-renewing cells, called tumor-initiating cells (TICs) or cancer stem cells (CSCs), are often resistant to therapy and can account for tumor relapse and progression in advanced PCa. With a FY11 PCRP-funded Synergistic Idea Development Award between three investigators and their laboratories at Rutgers Cancer Institute of New Jersey, Drs. Joseph Bertino, Isaac Kim, and Hatem Sabaawy combined their expertise in clinical oncology and stem cell biology to develop a novel therapy that specifically targets the TICs of PCa.

The multidisciplinary research team focused their strategies on identifying new small molecule inhibitors to target a stem cell growth factor called BMI-1. The researchers previously found that BMI-1 is overexpressed in prostate TICs and is essential for self-renewal and survival of TICs. To identify BMI-1 inhibitors, the team employed novel drug screening techniques that used fresh samples obtained directly from PCa patients. These primary samples were grown in cell culture, and in a zebrafish patient derived xenograft (Z-PDX) model which allowed for the testing of different doses and combinations of inhibitors in a small number of patient derived human PCa cells. These assays were also used to test the toxicity of the compounds and allowed them to focus on safer drugs. Once they identified an effective drug and dose in the Z-PDXs, they tested those compounds using more established mouse PDX models. Through this work, they identified the first known BMI-1 small molecule inhibitor, C-209, that successfully impaired TICs in primary cells, zebrafish, and mouse models of PCa.

Upon further testing, they found that the antitumor activities of the C-209 BMI-1 inhibitor were independent of prior treatment conditions. Furthermore, this inhibitor showed promise as both a monotherapy, or when combined with proliferation and hormonal-directed therapies for a more effective PCa treatment. These efforts to target BMI-1 in TICs paint a true picture of collaborative translational science to identify novel therapeutic options for those patients with advanced PCa.



Combinatorial effect of a MDA-7/IL-24-producting cancer terminator virus, Ad.tCCN1-CTV-m7, and small molecule inhibitor of Mcl-1, BI-97D6, in eradicating local and metastatic prostate cancer





Publications:

Bansal N, Bartucci M, Yusuff S et al. BMI-1 targeting interferes with patient-derived tumor-initiating cell survival and tumor growth in prostate cancer. Clin Cancer Res. 2016 Jun 15. pii: clincanres.310 PMID: 27307599

Bansal N, Davis S, Tereshchennko I et al. Enrichment of human prostate cancer cells with tumor initiating properties in mouse and zebrafish xenografts by differential adhesion. Prostate. 2014 Feb;74(2):187-200. doi: 10.1002/pros.22740


Public and Technical Abstract:

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

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Last updated Wednesday, December 28, 2016