P08.06 Transcriptional changes induced by bevacizumab combination therapy in responding and non-responding recurrent glioblastoma patients

Abstract

AbstractBackground:Bevacizumab combined with chemotherapy is among the most frequently used treatments in recurrent glioblastoma, and patients who achieve response to bevacizumab have improved survival as well as quality of life. The aim of this study was to investigate transcriptional changes associated with response and resistance to bevacizumab therapy.Material and Methods:The study included 21 recurrent glioblastoma patients who were response evaluable and had biomarker assessable tumor tissue surgically removed both before bevacizumab treatment and at time of progression. Patients were grouped into responders (n = 7) and non-responders (n = 14). Gene expression profiling of formalin-fixed paraffin-embedded tumor tissue was performed using RNA-sequencing. Differentially expressed genes were identified by comparing pretreatment samples of responders with those of non-responders and by pairwise comparison of pre- and posttreatment samples in responders and non-responders, separately. False discovery rate adjusted p-values < 0.05 were considered significant. Significant genes were analyzed by functional data mining.Results:There was no significant difference when comparing the transcriptional profile of responders with non-responders prior to initiation of bevacizumab therapy. In non-responders, we identified 1 differentially expressed gene using paired analysis of before and after treatment samples. In responders, this approach revealed 256 significantly differentially expressed genes of which 72 genes were down-regulated and 184 genes were up-regulated at time of progression. Genes differentially expressed in responders revealed a shift towards a more proneural and less mesenchymal phenotype at the time of progression. These transcriptional changes were found associated to inhibition of TGF-β1.Conclusion:Bevacizumab combination treatment is associated with significant transcriptional changes in responders but not in non-responders. This suggests that non-responders progress due to intrinsic resistance while responders progress due to acquired resistance. Our data suggests that responding glioblastomas undergoes a reverse mesenchymal shift at the time of recurrence, possibly related to down-regulation of TGF-β activity.