Therapy of prostate cancer using a novel cancer terminator virus and a small molecule BH-3 mimetic.
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 death correlated 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-24 promoted ER stress, decreased anti-apoptotic Mcl-1 expression and enhanced mda-7/IL-24 expression 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.
Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
Siddik
S
Sarkar
Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
Bridget A
BA
Quinn
Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
Xue-Ning
XN
Shen
Institute of Life Sciences, Chandrasekharpur, Bhubaneswar, Orissa, India.
Rupesh
R
Dash
Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
Swadesh K
SK
Das
Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
Luni
L
Emdad
Division of Cardiovascular Medicine and Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
Alexander L
AL
Klibanov
Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
Xiang-Yang
XY
Wang
Infectious and Inflammatory Disease Center, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
Maurizio
M
Pellecchia
Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
Devanand
D
Sarkar
Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
Paul B
PB
Fisher
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000067558:Biological Mimicry; D045744:Cell Line, Tumor; D055515:Cysteine-Rich Protein 61 / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006072:Gossypol / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008819:Mice, Nude; D008822:Mice, Transgenic; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy* / Q000821:virology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays; D000099180:Interleukin-24
D000970:Antineoplastic Agents; D055515:Cysteine-Rich Protein 61; D006072:Gossypol; D007378:Interleukins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D000099180:Interleukin-24; C474007:Bax protein (53-86); C579095:MCL1 protein, human; C492806:apogossypol; C534401:apogossypolone
BH3 mimetic; PEG-Prom; cancer terminator virus (CTV); prostate cancer (CaP); truncated CCN1 (tCCN1)-Prom