Work

Therapy of prostate cancer using a novel cancer terminator virus and a small molecule BH-3 mimetic

Year: 2015

Type: article

Abstract: // Siddik Sarkar 1 , Bridget A. Quinn 1 , Xue-Ning Shen 1 , Rupesh Dash 2 , Swadesh K. Das 1,3,4 , Luni Emdad 1,3,4 , Alexander L. Klibanov 5 , Xiang-Yang Wang 1,3,4 , Maurizio Pellecchia 6 , Devanand Sarkar 1,3,4 and Paul B. Fisher 1,3,4 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 Correspondence to: 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 Abstract 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-m 7, 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.3544