PMID- 37907716 OWN - NLM STAT- MEDLINE DCOM- 20231113 LR - 20231113 IS - 1573-7373 (Electronic) IS - 0167-594X (Print) IS - 0167-594X (Linking) VI - 165 IP - 1 DP - 2023 Oct TI - Decreased eukaryotic initiation factors expression upon temozolomide treatment-potential novel implications for eIFs in glioma therapy. PG - 91-100 LID - 10.1007/s11060-023-04451-y [doi] AB - PURPOSE: Since glioma therapy is currently still limited until today, new treatment options for this heterogeneous group of tumours are of great interest. Eukaryotic initiation factors (eIFs) are altered in various cancer entities, including gliomas. The purpose of our study was to evaluate the potential of eIFs as novel targets in glioma treatment. METHODS: We evaluated eIF protein expression and regulation in 22 glioblastoma patient-derived xenografts (GBM PDX) after treatment with established cytostatics and with regards to mutation profile analyses of GBM PDX. RESULTS: We observed decreased expression of several eIFs upon temozolomide (TMZ) treatment independent from the phosphatidylinositol 3-kinase (PI3K)/ AKT/ mammalian target of the rapamycin (mTOR) signalling pathway. These effects of TMZ treatment were not present in TMZ-resistant PDX. Combination therapy of regorafenib and TMZ re- established the eIF/AKT/mTOR axis. CONCLUSION: Our study provides novel insights into chemotherapeutic effects on eIF regulation in gliomas and suggests that eIFs are interesting candidates for future research to improve glioma therapy. CI - (c) 2023. The Author(s). FAU - Krassnig, Stefanie AU - Krassnig S AD - Diagnostic & Research Center for Molecular BioMedicine, Department of Neuropathology, Institute of Pathology, Medical University of Graz, Graz, Austria. FAU - Leber, Stefan L AU - Leber SL AD - Diagnostic & Research Center for Molecular BioMedicine, Department of Neuropathology, Institute of Pathology, Medical University of Graz, Graz, Austria. AD - Division of Neuroradiology, Vascular & Interventional Radiology, Department of Radiology, Medical University of Graz, Auenbruggerplatz 9, Graz, 8036, Austria. FAU - Orthmann, Andrea AU - Orthmann A AD - EPO Berlin Buch GmbH, Berlin, Germany. FAU - Golob-Schwarzl, Nicole AU - Golob-Schwarzl N AD - Diagnostic & Research Center for Molecular BioMedicine, Department of Neuropathology, Institute of Pathology, Medical University of Graz, Graz, Austria. AD - Center for Biomarker Research in Medicine, Graz, Austria. FAU - Huber, Heinrich Johann AU - Huber HJ AD - Drug Discovery Sciences, Dr. Boehringer Gasse 5-11 A-1121, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria. FAU - Wohlrab, Christina AU - Wohlrab C AD - Diagnostic & Research Center for Molecular BioMedicine, Department of Neuropathology, Institute of Pathology, Medical University of Graz, Graz, Austria. FAU - Skofler, Christina AU - Skofler C AD - Diagnostic & Research Center for Molecular BioMedicine, Department of Neuropathology, Institute of Pathology, Medical University of Graz, Graz, Austria. AD - Center for Biomarker Research in Medicine, Graz, Austria. FAU - Pennauer, Mirjam AU - Pennauer M AD - Diagnostic & Research Center for Molecular BioMedicine, Department of Neuropathology, Institute of Pathology, Medical University of Graz, Graz, Austria. FAU - Raicht, Andrea AU - Raicht A AD - Division of Paediatric Haematology and Oncology, Department of Paediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria. FAU - Birkl-Toeglhofer, Anna Maria AU - Birkl-Toeglhofer AM AD - Diagnostic & Research Center for Molecular BioMedicine, Department of Neuropathology, Institute of Pathology, Medical University of Graz, Graz, Austria. AD - Department of Pathology, Medical University of Innsbruck, Mullerstrasse 44, Innsbruck, 6020, Austria. FAU - Naumann, Michael AU - Naumann M AD - Institute of Experimental Internal Medicine, Otto Von Guericke University, Magdeburg, Germany. FAU - Mahdy-Ali, Kariem AU - Mahdy-Ali K AD - Department of Neurosurgery, Medical University of Graz, Graz, Austria. FAU - von Campe, Gord AU - von Campe G AD - Department of Neurosurgery, Medical University of Graz, Graz, Austria. FAU - Leoni, Marlene AU - Leoni M AD - Diagnostic & Research Center for Molecular BioMedicine, Department of Neuropathology, Institute of Pathology, Medical University of Graz, Graz, Austria. FAU - Alcaniz, Joshua AU - Alcaniz J AD - EPO Berlin Buch GmbH, Berlin, Germany. FAU - Hoffmann, Jens AU - Hoffmann J AD - EPO Berlin Buch GmbH, Berlin, Germany. FAU - Walchli, Thomas AU - Walchli T AD - Group of CNS Angiogenesis and Neurovascular Link, Neuroscience Center Zurich, Division of Neurosurgery, University and University Hospital Zurich, Zurich, Switzerland. AD - Division of Neurosurgery, University Hospital Zurich, Zurich, Switzerland. AD - Group Brain Vasculature and Perivascular Niche, Division of Experimental and Translational Neuroscience, Krembil Brain Institute, Toronto Western Hospital, University Health Network, Krembil Research Institute, University of Toronto, Toronto, ON, Canada. AD - Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada. FAU - Weis, Serge AU - Weis S AD - Division of Neuropathology, Kepler University Hospital, Johannes Kepler University, Neuromed Campus, Linz, Austria. FAU - Benesch, Martin AU - Benesch M AD - Division of Paediatric Haematology and Oncology, Department of Paediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria. FAU - Haybaeck, Johannes AU - Haybaeck J AD - Diagnostic & Research Center for Molecular BioMedicine, Department of Neuropathology, Institute of Pathology, Medical University of Graz, Graz, Austria. johannes.Haybaeck@tyrolpath.at. AD - Center for Biomarker Research in Medicine, Graz, Austria. johannes.Haybaeck@tyrolpath.at. AD - Department of Pathology, Medical University of Innsbruck, Mullerstrasse 44, Innsbruck, 6020, Austria. johannes.Haybaeck@tyrolpath.at. AD - Department of Pathology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany. johannes.Haybaeck@tyrolpath.at. AD - German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany. johannes.Haybaeck@tyrolpath.at. LA - eng PT - Journal Article DEP - 20231031 PL - United States TA - J Neurooncol JT - Journal of neuro-oncology JID - 8309335 RN - YF1K15M17Y (Temozolomide) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - 7GR28W0FJI (Dacarbazine) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Humans MH - Temozolomide/therapeutic use/pharmacology MH - Proto-Oncogene Proteins c-akt/metabolism MH - Phosphatidylinositol 3-Kinases/metabolism MH - Dacarbazine/therapeutic use/pharmacology MH - *Brain Neoplasms/genetics MH - Cell Line, Tumor MH - *Glioma/drug therapy/pathology MH - *Glioblastoma/drug therapy/pathology MH - TOR Serine-Threonine Kinases/metabolism PMC - PMC10638187 OTO - NOTNLM OT - Astrocytoma OT - Eukaryotic initiation factors OT - Glioma OT - Glioma therapy OT - Temozolomide COIS- J.Ho. is CEO and J.A. is an employee of EPO Berlin-Buch GmbH, Berlin, Germany. S.K., N.G.S., N.G. and J.H. hold a patent application on eIFs in gliomas. The remaining authors declare to have no competing interests. EDAT- 2023/11/01 06:43 MHDA- 2023/11/13 06:43 PMCR- 2023/10/31 CRDT- 2023/11/01 00:47 PHST- 2023/07/18 00:00 [received] PHST- 2023/09/12 00:00 [accepted] PHST- 2023/11/13 06:43 [medline] PHST- 2023/11/01 06:43 [pubmed] PHST- 2023/11/01 00:47 [entrez] PHST- 2023/10/31 00:00 [pmc-release] AID - 10.1007/s11060-023-04451-y [pii] AID - 4451 [pii] AID - 10.1007/s11060-023-04451-y [doi] PST - ppublish SO - J Neurooncol. 2023 Oct;165(1):91-100. doi: 10.1007/s11060-023-04451-y. Epub 2023 Oct 31.