Clinically relevant glioblastoma patient-derived xenograft models to guide drug development and identify molecular signatures.

Autor:	Alcaniz J; Experimental Pharmacology and Oncology GmbH, Berlin, Germany., Winkler L; Experimental Pharmacology and Oncology GmbH, Berlin, Germany., Dahlmann M; Experimental Pharmacology and Oncology GmbH, Berlin, Germany., Becker M; Experimental Pharmacology and Oncology GmbH, Berlin, Germany., Orthmann A; Experimental Pharmacology and Oncology GmbH, Berlin, Germany., Haybaeck J; Department of Neuropathology, Diagnostic & Research Center for Molecular BioMedicine, Institute of Pathology, Medical University of Graz, Graz, Austria.; Center for Biomarker Research in Medicine, Graz, Austria.; Institute of Pathology, Neuropathology, and Molecular Pathology, Medical University of Innsbruck, Innsbruck, Austria., Krassnig S; Department of Neuropathology, Diagnostic & Research Center for Molecular BioMedicine, Institute of Pathology, Medical University of Graz, Graz, Austria., Skofler C; Center for Biomarker Research in Medicine, Graz, Austria., Kratzsch T; Department of Neurosurgery, Charité Universitätsmedizin, Berlin, Germany., Kuhn SA; Department of Neurosurgery, Ernst von Bergmann Hospital, Potsdam, Germany., Jödicke A; Department of Neurosurgery, Vivantes Hospital Berlin Neukölln, Berlin, Germany., Linnebacher M; Department of Surgery, Molecular Oncology and Immunotherapy, University Medical Center Rostock, Rostock, Germany., Fichtner I; Experimental Pharmacology and Oncology GmbH, Berlin, Germany., Walther W; Experimental Pharmacology and Oncology GmbH, Berlin, Germany.; Max Delbrück Center for Molecular Medicine, Berlin, Germany.; Experimental and Clinical Research Center, Charité Universitätsmedizin, Berlin, Germany., Hoffmann J; Experimental Pharmacology and Oncology GmbH, Berlin, Germany.
Jazyk:	angličtina
Zdroj:	Frontiers in oncology [Front Oncol] 2023 Apr 11; Vol. 13, pp. 1129627. Date of Electronic Publication: 2023 Apr 11 (Print Publication: 2023).
DOI:	10.3389/fonc.2023.1129627
Abstrakt:	Glioblastoma (GBM) heterogeneity, aggressiveness and infiltrative growth drastically limit success of current standard of care drugs and efficacy of various new therapeutic approaches. There is a need for new therapies and models reflecting the complex biology of these tumors to analyze the molecular mechanisms of tumor formation and resistance, as well as to identify new therapeutic targets. We established and screened a panel of 26 patient-derived subcutaneous (s.c.) xenograft (PDX) GBM models on immunodeficient mice, of which 15 were also established as orthotopic models. Sensitivity toward a drug panel, selected for their different modes of action, was determined. Best treatment responses were observed for standard of care temozolomide, irinotecan and bevacizumab. Matching orthotopic models frequently show reduced sensitivity, as the blood-brain barrier limits crossing of the drugs to the GBM. Molecular characterization of 23 PDX identified all of them as IDH-wt (R132) with frequent mutations in EGFR, TP53, FAT1, and within the PI3K/Akt/mTOR pathway. Their expression profiles resemble proposed molecular GBM subtypes mesenchymal, proneural and classical, with pronounced clustering for gene sets related to angiogenesis and MAPK signaling. Subsequent gene set enrichment analysis identified hallmark gene sets of hypoxia and mTORC1 signaling as enriched in temozolomide resistant PDX. In models sensitive for mTOR inhibitor everolimus, hypoxia-related gene sets reactive oxygen species pathway and angiogenesis were enriched. Our results highlight how our platform of s.c. GBM PDX can reflect the complex, heterogeneous biology of GBM. Combined with transcriptome analyses, it is a valuable tool in identification of molecular signatures correlating with monitored responses. Available matching orthotopic PDX models can be used to assess the impact of the tumor microenvironment and blood-brain barrier on efficacy. Our GBM PDX panel therefore represents a valuable platform for screening regarding molecular markers and pharmacologically active drugs, as well as optimizing delivery of active drugs to the tumor. Competing Interests: JeH is CEO, WW is CSO, and JA, MB, MD and LW are employees of EPO Berlin-Buch GmbH, Berlin, Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Alcaniz, Winkler, Dahlmann, Becker, Orthmann, Haybaeck, Krassnig, Skofler, Kratzsch, Kuhn, Jödicke, Linnebacher, Fichtner, Walther and Hoffmann.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu