Abstract LB020: PTEN-L expressing HSV induces glioma stem cell differentiation and sensitizes glioblastoma to radiation in mice

Abstract

Abstract GBM, a WHO classified Grade IV glioma, is one of the most lethal and heterogeous primary brain tumors with inevitable recurrence, limiting the median survival time less than 21 months. Current standard-of-care treatment including surgical resection followed by chemo- and radio-therapy remains palliative because of therapy resistance, majorly conferred by GBM stem cells (GSCs), leading to tumor recurrence. With no current effective treatments, novel approaches to overcome GSCs-mediated resistance to chemotherapy and irradiation are urgently required in order to achieve long-term success in GBM therapy. Oncolytic viral (OV) therapy represents a novel and promising biological therapy for solid tumor that preferentially targets tumor cells for lytic destruction, sparing the healthy cells and in the process activating host anti-tumor immune response. Among all OVs, oncolytic Herpes Simplex Virus (oHSV) is substantially ahead in the clinic, with an oHSV T-VEC approved by the FDA for metastatic melanoma treatment. Recently, G47∆, another HSV1 virus, has been granted conditional approval for the treatment of GBM in Japan. Further, several other oHSVs including G207 and HSV1716 are currently being tested for safety and efficacy against GBM. This has fueled great expectations towards OVs as a promising alternative to conventional therapies. Our group has previously shown that PTENα expression by an oHSV (HSV-P10) resulted in further improved long-term survivors in intracranial tumor-bearing mice compared to HSVQ treatment. Here we aim to dissect the molecular mechanisms associated with improved therapeutic efficacy of HSV-P10 against GBM, and if HSV-P10 can overcome GBM cell radioresistance. The RNA sequencing and GSEA analyses of primary human GBM cells infected with control HSVQ or HSV-P10 reveals that while HSVQ virus infection leads to an increase in genes regulating IL6-STAT3 pathway, pivotal in maintaining stemness properties, HSV-P10 infection causes a reduction in the genes regulating this pathway. As a consequence, HSV-P10 reduces CD133+/CD44+ stem cell fraction, induces DNA damage and sensitizes the GBM cells to irradiation. Our findings reveal a novel mechanism induced by HSV-P10 in combination with irradiation whereby HSV-P10 modulates IL6-STAT3 signaling downregulating Sox2, a core transcription factor in the maintenance of GSCs, with a simultaneous decrease in Nestin expression and enhanced GFAP expression promoting GSC differentiation. HSV-P10 infection in combination with irradiation reduces GSC tumor sphere formation in vitro and sensitizes GBMs to radiotherapy in an intracranial mouse xenograft model. Collectively, our findings provide a potential avenue to overcome GSC-mediated therapy resistance to improve the therapeutic efficacy for GBM patients. Citation Format: Upasana Sahu, Matthew P. Mullarkey, Bangxing Hong, Balveen Kaur. PTEN-L expressing HSV induces glioma stem cell differentiation and sensitizes glioblastoma to radiation in mice [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 LB020.