ATPS-91GSK-3 INHIBITOR 9-ING-41 ENHANCES GENOTOXIC THERAPY OF GBM LEADING TO CURE FROM INTRACRANIAL BRAIN TUMOR

Abstract

BACKGROUND: Glycogen Synthase Kinase-3 (GSK-3), a positive regulator of NF-kappaB-mediated survival of cancer cells, has been identified as a potential therapeutic target for the treatment of GBM. We hypothesized that the inhibition of GSK-3 may overcome NF-kappaB-associated chemo- and radioresistance in human GBM. METHODS: We used GBM6 and GBM12 patient-derived xenograft (PDX) orthotopic tumor models, enabled for bioluminescence imaging (BLI) through luciferase modification, for evaluating the novel GSK-3 inhibitor 9-ING-41, when used in combination with genotoxic chemotherapy or radiotherapy. In vivo imaging system (IVIS) was used to study the effect of mono- and combination treatments, along with determination of survival benefit from treatment after intracranial transplantation of GBM tumor. RESULTS: BLI of animal subjects revealed that NF-kappaB is constitutively active in orthotopic GBM tumor expressing an NF-kappa luciferase reporter. Intravenous injection of 9-ING-41 significantly reduced the bioluminescence of orthotopic GBM PDX, indicative of reduced NF-kappaB transcriptional activity. When used in combination with the DNA alkylator CCNU, 9-ING-41 significantly increased CCNU anti-tumor activity against orthotopic GBM12 (no response to CCNU monotherapy) or GBM6 (partial response to CCNU monotherapy) xenografts, as indicated by the absence of tumor bioluminescence signal in mouse brain and by significantly increased animal subject survival. The treatment with CCNU + 9-ING-41 resulted in apparent cure for all mice with intracranial GBM6 and GBM12 tumors, as supported by histological evaluation that revealed a complete absence of cancer cells in mouse brain. CONCLUSIONS: Our results suggest that GSK-3 inhibitor 9-ING-41, a novel clinical drug candidate, enhances the efficacy of genotoxic therapy for human GBM, and warrants consideration for clinical evaluation. The combination of 9-ING-41 and radiotherapy, for the treatment of GBM12 orthotopic PDX tumors, is ongoing and will be presented.