SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3-BASED GLIOMA PATIENT STRATIFICATION AND APPLICATION IN PRECISION ONCOLOGY

Intratumoral heterogeneity is a hallmark of glioblastoma (GBM) tumors, thought to negatively influence therapeutic outcome. Previous studies showed that mesenchymal tumors fare more poorly than the proneural subtype. We focused on STAT3 because its activation precedes the proneural-mesenchymal transition. We first established a STAT3 gene signature that stratifies GBM patients into STAT3-high and -low cohorts. STAT3 inhibitor treatment selectively mitigated STAT3-high cell viability and tumorigenicity in orthotopic mouse xenograft models. Additionally, we defined the mechanism underlying resistance in STAT3-low cells by combining STAT3 signature analysis with kinome screen data on STAT3 inhibitor-treated cells. This allows us to draw connections between kinases affected by STAT3 inhibitors, their associated transcription factors and target genes. We demonstrate that dual inhibition of IGF-1R and STAT3 sensitized STAT3-low cells and improved survival in mice. Our study underscores the importance of serially profiling tumors so as to accurately target individuals who may demonstrate molecular subtype switching The mRNA extracted from STAT3 KD and NT GPCs, were hybridized on Affymetric HG U133Plus2 microarrays