Abstract LB128: Oncolytic HSV-P10 and effects on metabolism as potential therapy for treatment of glioblastoma

Abstract Glioblastoma is an aggressive tumor of the central nervous system associated with a very poor prognosis even with surgery and chemoradiation. We have previously developed an oHSV that encodes for PTENα (HSV-P10) and stimulates anti-tumor immunity. This virus is currently licensed by and is being developed by Mesoblast to evaluate safety and efficacy in patients. To understand the effect of PTENα on tumor cell responses to oHSV therapy we performed RNA sequencing of primary GBM cells infected with control or oHSV-P10. We identified a dysregulation of glycolysis in cells infected with oHSV-P10 relative to control oHSV. Since cancer cells rely heavily on glycolysis for energy production (Warburg effect) the impact of PTENα on metabolic switch was significant. RNA sequencing PCR and western blot analysis showed a significant reduction in cellular Hexokinase II expression and downregulation of HIF-1α in HSV-P10 infected cells. Consistent with the function of HIF1 and hexokinase in driving glycolysis we also observed a significant reduction in glucose uptake and lactate release: implying a reduction in glycolysis in cells after being treated with oHSV-P10. Thus, cellular energetics of HSV-P10 infected cells was directed away from glycolysis relative to HSVQ infected cells. Consistent with this we observed increased, oxidative phosphorylation, production of reactive oxidative species and ATP production. Many cancers, including Glioblastoma are known to utilize the glutamine as a substrate for energy production through its entry into the TCA cycle. Blocking this shows a significant decrease in cell viability and ATP production when combined with HSV-P10. These results indicate that combination of HSV-P10 with radiation has a significant therapeutic potential and should be tested in patients for safety and efficacy. Citation Format: Matthew P. Mullarkey, Upasana Sahu, Bangxing Hong, Balveen Kaur. Oncolytic HSV-P10 and effects on metabolism as potential therapy for treatment of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB128.