Helmholtz Gemeinschaft

Search
Browse
Statistics
Feeds

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

[thumbnail of Original Article]
Preview
PDF (Original Article) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
7MB
[thumbnail of Supplementary Material] Other (Supplementary Material)
3MB

Item Type:Article
Title:Clinically relevant glioblastoma patient-derived xenograft models to guide drug development and identify molecular signatures
Creators Name:Alcaniz, J., Winkler, L., Dahlmann, M., Becker, M., Orthmann, A., Haybaeck, J., Krassnig, S., Skofler, C., Kratzsch, T., Kuhn, S.A., Jödicke, A., Linnebacher, M., Fichtner, I., Walther, W. and Hoffmann, J.
Abstract: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.
Keywords:Glioblastoma, Glioma, Patient-Derived Xenograft (PDX), Preclinical Oncology, Drug Efficacy, Targeted Therapy, Blood-Brain Barrier, mTORC1, Animals, Mice
Source:Frontiers in Oncology
ISSN:2234-943X
Publisher:Frontiers Media SA
Volume:13
Page Range:1129627
Date:11 April 2023
Official Publication:https://doi.org/10.3389/fonc.2023.1129627
PubMed:View item in PubMed

Repository Staff Only: item control page

Downloads

Downloads per month over past year

Open Access
MDC Library