Effect of decorin on overcoming the extracellular matrix barrier for oncolytic virotherapy

Abstract

The pressing challenge for contemporary gene therapy is to deliver enough therapeutic genes to enough cancer cells in vivo. With the aim of improving viral distribution and tumor penetration, we explored the use of decorin to enhance viral spreading and tumor tissue penetration. We generated decorin-expressing replication-incompetent (dl-LacZ-DCNG, dl-LacZ-DCNQ and dl-LacZ-DCNK) and replication-competent (Ad-DE1B-DCNG, Ad-DE1B-DCNQ and Ad-DE1B-DCNK) adenoviruses (Ads). Point mutants of decorin gene (DCNG), DCNK and DCNQ, have a negative and moderate binding affinity to type-I collagen fibril, respectively. In both tumor spheroids and established solid tumors in vivo, tissue penetration potency of dl-LacZ-DCNG was greatly enhanced than those of dl-LacZ, dl-LacZ-DCNQ and dl-LacZ-DCNK, and this enhanced tissue penetration effect derived from decorinexpressing Ad was dependent on the binding affinity of decorin to collagen fibril. Expression of DCNG enhanced viral spread of replicating Ad, leading to improved tumor reduction and survival benefit. Moreover, the tumoricidal effects of Ad-DE1B-DCNQ and Ad-DE1B-DCNK were lessened, as the binding affinity to collagen was decreased, showing that the increased cancer cell cytotoxicity was driven by the action of decorin on extracellular matrix (ECM). Furthermore, Ad-DE1B-DCNG substantially decreased ECM components within the tumor tissue. Finally, intratumoral injection of Ad-DE1B-DCNG in primary tumor site greatly reduced the formation of B16BL6 melanoma cell pulmonary metastases in mice. Taken together, these data show the utility of decorin as a dispersion agent and highlight its utility and potential in improving the efficacy of replicating Ad-mediated cancer gene therapy.

Safety and Efficacy of VCN-01, an Oncolytic Adenovirus Combining Fiber HSG-Binding Domain Replacement with RGD and Hyaluronidase Expression

“…Different modulators of ECM such as decorin, relaxin, metalloprotease 9, or chondroitinase ABC have been used to increase viral spread and antitumor efficacy in different tumor types taking into account specific ECM compositions (16)(17)(18)(19)(20). High levels of HA are present in almost 87% of pancreatic adenocarcinomas (22,47), and hyaluronidase expression by VCN-01 can provide a particular advantage to treat this tumor type.…”

“…To tackle this problem, oncolytic viruses have been armed with ECM-degrading enzymes such as relaxin, decorin, metalloprotease-9, chondroitinase ABC (16)(17)(18)(19)(20), or PH20 hyaluronidase as we have previously reported (21). In addition, recombinant hyaluronidase enhances the penetration and efficacy of several chemotherapeutic agents including docetaxel, doxorubicin, or gemcitabine, presumably due to a reduction of the IFP in tumors (22)(23)(24).…”

Strategies to Enhance Viral Penetration of Solid Tumors

“…These results translated into more effective control of tumor growth in vivo and better survival when using the decorin-expressing virus as compared with treatment with the parental virus. Immunohistochemistry also showed that tumors treated with decorin-expressing adenovirus had significantly reduced collagen types I and III and elastin as compared with controls (Choi et al, 2010).…”

Current advances in adenovirus nanocomplexes: more specificity and less immunogenicity

“…Circulation of naked Ad in the blood causes acute viral accumulation and hepatocytosis in the liver, resulting in undesired gene expression and an inappropriate innate immune response. To avoid activating immune responses and hepatotoxicity, an effective Ad nanocomplex delivery system for systemic tumor therapy has been used for minimal hepatic distribution and high localization in tumor cells (10)(11)(12). This review describes the recent developments in the design of cancer-targeted Ad nanocomplexes to overcome limited systemic delivery efficiency and inappropriate triggering of immune responses, thereby enhancing the efficacy and safety of anti-cancer therapeutic strategies.…”