Preclinical Evaluation of Differentially Targeting Dual Virotherapy for Human Solid Cancer

Abstract

Multimodal approaches combining drugs that differentially function is the most popular regimen for treating human cancer. Understanding the molecular mechanisms underlying the synergistic, potentiative, and antagonistic effects of drug combinations could facilitate the discovery of novel efficacious combinations. We previously showed that telomerase-specific replication-competent adenovirus (Telomelysin,, in which the human telomerase reverse transcriptase promoter controls the adenoviral E1 gene expression, induces a selective antitumor effect in human cancer cells. Here, using E1-deleted replicationdeficient adenovirus expressing the p53 tumor suppressor gene (Advexin, Ad-p53) and OBP-301, we investigate how these adenoviruses that kill tumor cells with different mechanisms could work in combination on human cancer. We found that E1-deficient Ad-p53 could kill cancer cells more efficiently in the presence of OBP-301 than Ad-p53 alone or OBP-301 alone, because Ad-p53 could become replication-competent by being supplied adenoviral E1 from coinfected OBP-301 in trans. Ad-p53 plus OBP-301 induced high levels of p53 protein expression without p21 induction, resulting in apoptotic cell death documented by active caspase-3 expression with a cytometric bead array and an increased subdiploid apoptotic fraction of the cell cycle. For in vivo evaluation, nude mice xenografted with human lung tumors received intratumoral injection of OBP-301 and/or Ad-p53. Analysis of the growth of implanted tumors showed an enhanced antitumor effect in combination therapy. Our data show that Ad-p53 in combination with OBP-301 induces not only oncolytic but also apoptotic cancer cell death and enhances antitumor activity in vitro and in vivo, providing potential merits as a multimodal treatment for human cancer.

Dual Programmed Cell Death Pathways Induced by p53 Transactivation Overcome Resistance to Oncolytic Adenovirus in Human Osteosarcoma Cells

“…We recently reported that combination therapy with OBP-301 and Adp53 resulted in a more profound antitumor effect than monotherapy with either OBP-301 or Ad-p53 (25). Moreover, we generated armed OBP-301 expressing the wildtype p53 tumor suppressor gene (OBP-702) and showed that OBP-702 suppressed the viability of various types of epithelial malignant cells more efficiently than did OBP-301 (26).…”

Telomere and Telomerase Therapeutics in Cancer

“…Upon infection, E1A and E1B are expressed and induce viral replication and cellular lysis in TERT promoter active tumor cells, while sparing TERT promoter inactive benign cells [ 160 ]. In vitro , the oncolytic virus OBP-301 (telomelysin) has been shown to selectively lyse lung cancer cells [ 161 ], kill CD133+ human gastric cancer stem-like cells [ 162 ], and inhibit lung tumor xenografts treated with direct intratumoral injection [ 163 ]. In phase I testing, OBP-301 was well tolerated at three different dose levels with no serious adverse events [ 136 ].…”

Evolving Therapies and FAK Inhibitors for the Treatment of Cancer

“…For example, AD5CMV-p53 is an adenoviral vector encoding p53 that was shown to replenish p53 in p53 deficient tumor cells. This approach inhibited lung cancer cell growth both in vitro and in vivo [141]. Clinical phase I and II trials have subsequently demonstrated that this agent is both safe and effective against esophageal squamous cell carcinoma [142, 143].…”