Abstract 4227: PARP inhibitors sensitize glioblastoma stem cells to oncolytic herpes simplex virus therapy

Abstract

Abstract Glioblastoma (GBM) is an invariably fatal brain tumor in adults and remains a great challenge for preclinical and clinical research. PARP inhibitors (PARPi) have been used alone or in combination with genotoxic agents for the treatment of cancers with homologous recombination (HR) repair deficiencies. Oncolytic herpes simplex viruses (oHSVs) are genetically-engineered to selectively replicate in cancer cells, and previous studies have shown that oHSV infection of glioblastoma stem cells (GSC) induces DNA damage and compromises HR DNA repair. Therefore, we hypothesized that PARPi and oHSV would synergistically kill GSCs through inducing lethal DNA damage. Here, we show that PARPi consistently inhibited PARylation in a panel of patient-derived GSC lines. Surprisingly, half of GSCs (4 of 8) were sensitive to PARPi killing, with the other half being resistant. When combined with 2 different oHSVs, MG18L and G47Δ, PARPi olaparib and oHSV synergistically killed olaparib-sensitive GSCs in vitro. Moreover, olaparib sensitized PARPi-resistant GSCs to the cytotoxic effects of MG18L or G47Δ, leading to increased DNA damage and cell death. While monotherapy with systemic olaparib or intratumoral injection of MG18L increased survival in an orthotopic xenograft model generated with olaparib-sensitive GSCs, combination treatment greatly extended survival over either monotherapy alone, with concomitant induction of robust DNA damage and apoptosis in the tumors. Furthermore, in an orthotopic model with olaparib-resistant GSCs, in which olaparib monotherapy was not effective, combinatorial therapy of olaparib and MG18L was significantly more efficacious than MG18L alone in prolonging lifespan. Our studies demonstrate that PARPi have anti-GSC activity in about half of GBMs tested, and combining PARPi with oHSV targets DNA damage responses and induces a synthetic lethal effect in vitro and in vivo against both PARPi-sensitive and -resistant GSCs. This report describes a new therapeutic strategy for GBM and supports investigations of this combination in the clinic. Citation Format: Jianfang Ning, Hiroaki Wakimoto, Robert Martuza, Samuel Rabkin. PARP inhibitors sensitize glioblastoma stem cells to oncolytic herpes simplex virus therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4227. doi:10.1158/1538-7445.AM2015-4227