Investigating the effects of the FGFR3-TACC3 fusion in brain tumors
Glioblastoma multiforme (GBM) is an aggressive and malignant form of brain cancer with a generally poor prognosis. Targeted treatments have shown limited activity in gliomas due to tumor heterogeneity and the blood-brain barrier (BBB). Genomic profiling studies have expanded our understanding of the genomic alterations frequently seen in gliomas. We hypothesize that proteomic and phosphoproteomic profiling of tumors can provide additional insight into activated pathways in these tumors and enable identification of new therapeutic targets. We focused on the FGFR3-TACC3 fusion, an alteration that occurs in a subset of gliomas. Using publicly available Reverse Phase Protein Array data from The Cancer Genome Atlas, we investigated upregulated pathways in two FGFR3-TACC3 fusion positive low grade gliomas. We found both tumors showed activation of pathways downstream of FGFR3, including MAPK, PI3K, and PKC. One tumor showed high levels of PKC activation and the other tumor showed high levels of PI3K/mTOR activation. We next investigated inhibitors of these pathways and assessed their ability to penetrate the BBB using the Central Nervous System Multiparameter Optimization calculator. We identified one PKC inhibitor (Sotrastaurin) and two mTOR inhibitors (Sapanisertib and Samotolisib) predicted to cross the BBB. Together, these results demonstrate the added value of incorporating phosphoproteomic analysis when molecularly profiling tumors.
