Priority Research Papers:
Therapy of prostate cancer using a novel cancer terminator virus and a small molecule BH-3 mimetic
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Siddik Sarkar1, Bridget A. Quinn1, Xue-Ning Shen1, Rupesh Dash2, Swadesh K. Das1,3,4, Luni Emdad1,3,4, Alexander L. Klibanov5, Xiang-Yang Wang1,3,4, Maurizio Pellecchia6, Devanand Sarkar1,3,4 and Paul B. Fisher1,3,4
1 Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
2 Institute of Life Sciences, Chandrasekharpur, Bhubaneswar, Orissa, India
3 VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
4 VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
5 Division of Cardiovascular Medicine and Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
6 Infectious and Inflammatory Disease Center, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA
Paul B. Fisher, email:
Keywords: BH3 mimetic, cancer terminator virus (CTV, prostate cancer (CaP), truncated CCN1 (tCCN1)-Prom, PEG-Prom
Received: January 02, 2015 Accepted: February 16, 2015 Published: March 12, 2015
Despite recent advances, treatment options for advanced prostate cancer (CaP) remain limited. We are pioneering approaches to treat advanced CaP that employ conditionally replication-competent oncolytic adenoviruses that simultaneously produce a systemically active cancer-specific therapeutic cytokine, mda-7/IL-24, Cancer Terminator Viruses (CTV). A truncated version of the CCN1/CYR61 gene promoter, tCCN1-Prom, was more active than progression elevated gene-3 promoter (PEG-Prom) in regulating transformation-selective transgene expression in CaP and oncogene-transformed rat embryo cells. Accordingly, we developed a new CTV, Ad.tCCN1-CTV-m7, which displayed dose-dependent killing of CaP without harming normal prostate epithelial cells in vitro with significant anti-cancer activity in vivo in both nude mouse CaP xenograft and transgenic Hi-Myc mice (using ultrasound-targeted microbubble (MB)-destruction, UTMD, with decorated MBs). Resistance to mda-7/IL-24-induced cell deathcorrelated with overexpression of Bcl-2 family proteins. Inhibiting Mcl-1 using an enhanced BH3 mimetic, BI-97D6, sensitized CaP cell lines to mda-7/IL-24-induced apoptosis. Combining BI-97D6 with Ads expressing mda-7/IL-24promoted ER stress, decreased anti-apoptotic Mcl-1 expression and enhanced mda-7/IL-24expression through mRNA stabilization selectively in CaP cells. In Hi-myc mice, the combination induced enhanced apoptosis and tumor growth suppression. These studies highlight therapeutic efficacy of combining a BH3 mimetic with a novel CTV, supporting potential clinical applications for treating advanced CaP.
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