Abstract 4674: Patient-derived xenograft (PDX) and corresponding cell line models from glioblastoma for drug development, immuno-oncology and translational research
Authors: Alcaniz Joshua , Winkler Lars , Stecklum Maria , Wieland Hagen , Siegert Antje , Becker Michael , Brzezicha Bernadette , Walther Wolfgang , Hoffmann Jens 
Published: April 2023

Abstract
Background: Glioblastoma (GBM) is the most common malignant brain tumor in adults, with about 90% of tumors developing de novo. Their heterogeneity, aggressiveness and infiltrative growth limit success of current standard of care (SoC) therapy and efficacy of new therapeutic approaches. For drug development a large panel of patient-derived tumor cell models is needed to generate most comparable in vitro and in vivo platform reflecting the complex biology of glioblastoma. Glioblastoma cell lines from patient-derived xenografts (PDX) preserve many patient specific characteristics and to perform the essential steps of pre-clinical drug development from in vitro screening to orthotopic in vivo approaches under conditions, which closely resemble the clinical situation. Further, GBM PDX models are useful for immune oncology research.
Methods: A panel of 26 glioblastoma PDX models was established on immunodeficient mice (15 out of these established orthotopically). All models were characterized for drug sensitivity and molecular profile using panel and transcriptome sequencing. From these, three corresponding tumor cell lines were successfully established and characterized. Quality and identity of the models was performed by FACS and PCR analysis. Expression profile, drug sensitivity and growth behavior was determined and compared in vitro and after re-transplantation in vivo with the original PDX glioma model. In addition, we employed GBM PDX models for checkpoint-inhibitor sensitivity in humanized mouse settings.
Results: Drug testing was performed in s.c. and orthotopic models revealed, that best treatment responses in s.c. models (tumor growth inhibition &gt; 50%) were observed for SoC temozolomide (TMZ), irinotecan and bevacizumab. Molecular characterization identified all our models as IDH-wt (R132) with frequent mutations in PARP1, EGFR, TP53, FAT1, and within the PI3K/AKT/mTOR pathway. Their expression profiles resemble proposed mesenchymal, proneural and classical GBM molecular subtypes. Further, treatment of GBM PDX with ipilimumab, nivolumab or pembrozolumab generated minor growth delay.
Conclusions: In drug sensitivity screening, irinotecan or bevacizumab were identified as alternative treatment options in TMZ resistant GBM PDX models. Our data demonstrate, that the established platform of s.c. and orthotopic GBM PDX is valuable for drug development and can well be complemented by a PDX-derived cell lines for in vitro screens. Furthermore, these models can be used for the evaluation of new immune-oncology therapies.
Citation Format: Joshua Alcaniz, Lars Winkler, Maria Stecklum, Hagen Wieland, Antje Siegert, Michael Becker, Bernadette Brzezicha, Wolfgang Walther, Jens Hoffmann. Patient-derived xenograft (PDX) and corresponding cell line models from glioblastoma for drug development, immuno-oncology and translational research. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4674.