Abstract LB-140: Targeting brain tumour initiating cells using a dual-pronged approach of oncolytic virotherapy and chemotherapeutics

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL BACKGROUND: Brain tumour initiating cells (BTICs) are stem-like cells hypothesized to mediate tumorigenesis and recurrence in glioblastoma multiforme (GBM). Patient-derived BTICs represent highly relevant preclinical GBM models, forming aggressive, infiltrative tumours in nude mice that closely recapitulate the phenotypic heterogeneity of patient GBMs. BTICs have also been shown to possess mechanisms mediating both chemo- and radio-resistance. Recently, success has been demonstrated in treating BTICs with oncolytic virotherapy (OV), which uses replication-competent viruses to specifically target and kill malignant cells. Myxoma virus (MyxV) is a promising oncolytic candidate, which our lab has shown to be highly efficacious in preclinical GBM models, effectively curing GBM xenografts with a single intra-cranial injection. By contrast, long-term survival is not obtained in MyxV-treated, BTIC-tumour-bearing mice, though survival is prolonged. HYPOTHESIS: We hypothesize that MyxV treatment of BTICs can be improved by utilizing clinically relevant chemotherapeutics identified via high-throughput pharmacoviral screens. RESULTS: We utilized a diverse, comprehensive panel of 80 small molecule inhibitors with preclinical and clinical anti-cancer efficacy to screen for synergy with MyxV treatment in vitro. Multiple candidates have been identified and are currently being validated for synergy (Chou-Talalay method) using a panel of genetically distinct, patient-derived BTICs. Our results implicate multiple potential targets for OV combination therapy, including topoisomerase I and the PI-3K/Akt/mTOR pathway. Target validation is currently underway using shRNA knockdowns and additional targeted inhibitors of these pathways. Further, the mechanism of synergistic cell death during these combination treatments is being explored. In vivo experiments utilizing the dual-pronged pharmacoviral approach are also underway. SIGNIFICANCE: We describe the nature and identity of compounds that carry the potential to sensitize BTICs to MyxV infection. Our findings offer an effective avenue to elucidate resistance mechanisms and develop efficacious combination therapies for targeting disease reservoirs within highly refractory GBMs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-140. doi:1538-7445.AM2012-LB-140