gms | German Medical Science

Objective: Development of a molecular guided approach for individualized selection of chemotherapeutics in (recurrent) GBM. In this EU-funded project high-throughput RNA sequencing and bioinformatics were utilized to quantitatively analyze activities of oncopathways involved in response to FDA-approved chemotherapeutics.

Methods: Biopsy material from primary and recurrent GBM was used for RNA sequencing (RNA-seq) and establishing primary cultures of glioma stem cells (GSCs), which were then examined in the same way. RNA-seq data were subjected to analyses of differential gene expression (DE) and quantitative pathway activation analysis using Oncobox – an original bioinformatic tool developed at Oncobox (http://www.oncobox.com/). Results for primary and recurrent GBM were compared. Oncobox analysis was further used to model the efficacy of 130 FDA-approved anti-cancer drugs.

Results: 128 tissue samples and 42 GSC cultures from 44 GBMs were analyzed. 23 primary GBM, 19 recurrent cases and 2 secondary recurrent GBMs were included. In 14 cases matching pairs of primary and recurrent GBM could be obtained. DE analysis revealed a high degree of concordance between tumor tissues and GSCs in the longitudinal transcriptomic changes associated with tumor recurrence. Oncobox analysis showed downregulation of key pathways involved in the regulation of DNA repair and upregulation of immune pathways in recurrent GBM compared to the corresponding primary tumors. When specifically looking at pathways involved in response to chemotherapeutics we found a downregulation of pathways targeted by Temozolomide and Lomustine in recurrent GBM. In contrast, several pathways showed a significant (p<0.05) increase in their activities in the setting of recurrence. Interestingly, among the upregulated pathways those targeted by chemotherapeutics currently investigated in phase II or III trials on GBM (Durvalumab or Pomalidomide) were also found upregulated in recurrent tumors.

Conclusion: Our study suggests that the spectrum of potentially effective drugs may differ between newly diagnosed and recurrent glioblastomas and provides a transcriptional rationale for the lack of significant therapeutic benefit from temozolomide in patients with recurrent glioblastoma. The approach carries the potential of predicting sensitivity to specific chemotherapeutics and might be used for individual optimization of treatment regimes.