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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Therapy of prostate cancer using a novel cancer terminator virus and a small molecule BH-3 mimetic
Siddik Sarkar1, Bridget A Quinn1, Xue-Ning Shen1
1Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
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-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.
Insights
A novel Cancer Terminator Virus (CTV) combined with a BH3 mimetic effectively targets advanced prostate cancer (CaP) by inducing apoptosis and suppressing tumor growth, offering a promising new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Advanced prostate cancer (CaP) treatment options are limited.
- Oncolytic adenoviruses producing mda-7/IL-24 (Cancer Terminator Viruses, CTV) are a novel therapeutic approach.
- Targeted gene expression regulation is crucial for selective cancer cell killing.
Purpose of the Study:
- To develop and evaluate a novel CTV, Ad.tCCN1-CTV-m7, utilizing a truncated CCN1 promoter for enhanced cancer-specific transgene expression.
- To investigate the combination therapy of this novel CTV with a BH3 mimetic (BI-97D6) to overcome resistance and enhance apoptosis in advanced CaP.
- To assess the therapeutic efficacy of the combined approach in preclinical models of prostate cancer.
Main Methods:
- Development of a new CTV, Ad.tCCN1-CTV-m7, using a truncated CCN1 promoter (tCCN1-Prom).
- In vitro and in vivo evaluation of Ad.tCCN1-CTV-m7 in prostate cancer models.
- Combination therapy using Ad.tCCN1-CTV-m7 and the BH3 mimetic BI-97D6.
- Assessment of apoptosis, ER stress, and gene expression changes in cancer cells.
Main Results:
- Ad.tCCN1-CTV-m7 demonstrated dose-dependent killing of CaP cells in vitro and anti-cancer activity in vivo.
- Resistance to mda-7/IL-24 was linked to Bcl-2 family protein overexpression.
- The combination of BI-97D6 and Ad.tCCN1-CTV-m7 enhanced apoptosis, ER stress, and tumor suppression in CaP models.
- BI-97D6 sensitized CaP cells to mda-7/IL-24 by inhibiting Mcl-1 and stabilizing mda-7/IL-24 mRNA.
Conclusions:
- The novel CTV, Ad.tCCN1-CTV-m7, shows selective and potent anti-cancer activity.
- Combining a BH3 mimetic with a CTV is a viable strategy to enhance therapeutic efficacy in advanced prostate cancer.
- This combination therapy holds potential for clinical application in treating advanced CaP.
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