The Potential of Conditionally Replicating Adenovirus Expressing TIMP2 for Ovarian Cancer Therapy

Abstract

Current therapies for ovarian cancer have limited prognostic outcome due to advanced stage of the disease at diagnosis. Among new therapies, conditionally replicating adenoviruses (CRAds), designed to selectively lyse cancer cells, hold promise. However in clinical trials, CRAds exhibit limited efficacy thus far. Second generation CRAds are being developed to express a therapeutic protein to enhance antitumor efficacy. One attractive target in the tumor microenvironment is the matrix metalloproteinases (MMPs). MMPs are endogenous proteases that degrade ECM and are upregulated in ovarian cancer. Tissue inhibitors of metalloproteinase 2 (TIMP2) is an endogenous inhibitor of MMPs. The present study developed a CRAd that uses the CXCR4 promoter for enhanced replication combined with the inclusion of the TIMP2 transgene. Transductional selectivity is further achieved by replacement of the Ad5 knob with the Ad3 knob, whose receptor is overexpressed on ovarian cancer cells. To evaluate the expression profile of this armed CRAd, human ovarian cancer cells were infected with Ad5/3‐CXCR4‐TIMP2. The TIMP2 produced was functional, as demonstrated by the inhibition of MMP activity. Further validation of this virus on primary ovarian cancer tissues obtained from patients revealed high levels of viral replication, suggesting the potential of this vector for ovarian cancer therapy.