Abstract 7241: Combination of CDK4/6 inhibitor promotes the antitumor effect of oncolytic adenovirus against canine breast cancer cells

Abstract

Abstract Background: Oncolytic virotherapy has emerged as a novel antitumor platform to induce tumor-specific cytopathic effect against human cancer cells. However, whether oncolytic virotherapy is effective to canine cancer cells remains unclear. We developed telomerase-specific oncolytic adenoviruses OBP-301 and a p53-armed OBP-702 based on human adenovirus serotype 5. OBP-301 and OBP-702 have therapeutic potential against various types of human cancer cells. As recent report has suggested that human adenovirus serotype 5 induces cytopathic effect against canine cancer cells, OBP-301 and OBP-702 are expected to have therapeutic effects against canine cancer cells. Furthermore, it has been reported that CDK4/6 inhibitors clinically used for human breast cancers promote the replication of oncolytic adenoviruses, suggesting that combination of CDK4/6 inhibitors promote the therapeutic potential of oncolytic adenoviruses. In this study, we investigated the therapeutic potential of OBP-301 and OBP-702 against canine breast cancer cells in monotherapy and combination therapy with CDK4/6 inhibitor. Methods: Two canine breast cancer cell lines (CMT-U27, AZA-CB) were used in this study. The antitumor effect of OBP-301 and OBP-702 against canine breast cancer cells was analyzed using the XTT assay. The therapeutic potential of combination therapy with CDK4/6 inhibitor (palibociclib) was further analyzed. Virus-mediated induction of adenovirus E1A and p53 expression was analyzed by Western blotting. The in vivo antitumor effects of OBP-301 and OBP-702 were assessed using CMT-U27 subcutaneous tumor model. Results: OBP-301 and OBP-702 had cytopathic effect against CMT-U27 and AZA-CB cells. The antitumor activity of OBP-702 was superior to that of OBP-301. The combination of palbociclib and OBP-301 showed a more profound antitumor effect compared with monotherapy against CMT-U27 and AZA-CB cells. The expression of E1A and p53 was increased in virus-treated CMT-U27 and AZA-CB cells in a dose-dependent manner. Intratumoral administration of OBP-301 and OBP-702 significantly suppressed the growth of subcutaneous CMT-U27 tumors compared with mock treatment. Conclusion: Our results suggest that telomerase-specific oncolytic adenoviruses have cytopathic effect against canine breast cancer cells via virus infection and replication. Furthermore, combination of CDK4/6 inhibitor may be a promising strategy for promoting the antitumor effect of oncolytic adenovirus against canine breast cancers. Citation Format: Naoyuki Hashimoto, Hiroshi Tazawa, Satoru Kikuchi, Shinji Kuroda, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara. Combination of CDK4/6 inhibitor promotes the antitumor effect of oncolytic adenovirus against canine breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7241.