Year-end Sale % OFF 
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.
Highlights
Prostate cancer (CaP) is the leading cause of cancer deaths in men in the USA despite improvements in chemo, radio, and hormonal-therapies
In the ARCaP series of CaP cells, ARCaP-M cells derived from androgen repressed human CaP (ARCaP) cells with bone metastatic capacity in vivo and a mesenchymal phenotype had higher tCCN1-Prom expression as compared to its epithelial-like counterpart, ARCaP-E (Fig. 1B)
In metastatic cells, e.g., PC3, PC-3ML and ARCaP-M, tCCN1-Prom activity was significantly higher than the cancer-specific PEG-Prom [35], which shows elevated cancer-specific expression in human CaP cells (Fig. 1B)
Summary
Prostate cancer (CaP) is the leading cause of cancer deaths in men in the USA despite improvements in chemo-, radio-, and hormonal-therapies. When CaP has metastasized to bones and distant organs [1]. It is imperative to find a means of preventing or treating CaP after it has metastasized. Some success in treating advanced CaP patients with bone metastases has been achieved using external beam radiation therapy, hormonal-therapy and chemotherapy with bisphosphonates, which target bone remodeling www.impactjournals.com/oncotarget [2]. The effectiveness of these combination treatment strategies appeared promising they were limited to the areas of bone they target and were ineffective at later stages of metastasis. The side effects of current treatment approaches mandate innovative and improved strategies to treat CaP, especially advanced CaP
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
