Abstract 5000: YB-1 based oncolytic virotherapy in combination with small molecular inhibitors for treatment of refractory osteosarcoma

Abstract

Abstract This in vitro study evaluates YB-1 based oncolytic virotherapy in combination with molecular target therapy as a novel therapeutic strategy for refractory osteosarcoma. In vitro combination approaches include CDK4/6-, MDM2- and PARP-inhibitors. The treatment strategy was explored in four established osteosarcoma cell lines (143B, MG-63, SJSA, U2OS). Intracellular YB-1 expression was evaluated by immunofluorescence for oncolytic therapy with YB-1 selective adenovirus XVir-N-31. Efficacy of mono- and combination therapy is assessed using cell survival assays. The Chou Talalay method is used to determine synergistic effects between combinational components. Characterization of molecular pathways associated with oncolytic cytotoxicity is done using cell cycle analysis, western blotting, hexon titer test, sqPCR and ELISA. We observe a potent preclinical anti-tumor effect using XVir-N-31 monotherapy on all tested osteosarcoma cell lines. However, most cell lines were resistant towards inhibitor monotherapy in clinically achievable concentrations. In contrast, all dual combinations resulted in significantly enhanced cytotoxicity. These results require reduced numbers of infectious viral particles and are observed at clinically implementable inhibitor concentrations. Increased oncolytic cytotoxicity is associated with changes of tumor cell cycle regulation due to inhibitor treatment and modulation of infectious viral particle formation. In summary, we determine XVir-N-31 as a potent oncolytic agent for the treatment of refractory osteosarcoma. We provide a strong preclinical rationale for the combination of oncolytic adenovirus with molecular target therapy. A phase I clinical trial with XVir-N-31 in combination with molecular target therapy for refractory childhood sarcoma is planned. Citation Format: Charlotte Friederike Middendorf, Sebastian Johannes Schober, Corazón Kordass, Roman Nawroth, Stefan E. Burdach, Per Sonne Holm, Uwe Thiel. YB-1 based oncolytic virotherapy in combination with small molecular inhibitors for treatment of refractory osteosarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5000.