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CSIG-03. STAT3-BASED PATIENT STRATIFICATION IN PRECISION NEURO-ONCOLOGY


 Glioblastoma (GBM) displays both spatial and temporal heterogeneity, whereupon mesenchymal tumors fare more poorly than the proneural molecular subtype. STAT3 was selected because its activation preceeds the proneural-mesenchymal transition. We first defined a STAT3 gene signature that stratified GBM patients into STAT3-high and -low cohorts. STAT3 inhibitor treatment selectively mitigated STAT3-high cell viability and tumorigenicity in orthotopic mouse xenograft models. In addition, we elucidated the mechanism underlying resistance in STAT3-low cells by combining STAT3 signature analysis with kinome screen data on STAT3 inhibitor-treated cells, allowing us to draw connections between kinases affected by STAT3 inhibitors, their associated transcription factors and target genes. As such, we show that dual inhibition of IGF-1R and STAT3 sensitized STAT3-low cells and improved survival in mice. Our study emphasizes the clinical implications of molecular subtype switching and demonstrates the importance of serially profiling GBM tumors upon recurrence so as to facilitate effective therapy.