Altered signaling pathways and inhibitors. Receptor tyrosine kinase (RTK), EGFR and platelet-derived growth factor receptor (PDGFR) are receptor tyrosine kinases (RTKs). In GBM, 40–60% of cases exhibit EGFR amplification and high EGFR protein expression levels. PDGFR is overexpressed at the transcriptional level. EGFR activation initiates signal transduction such as the PI3K/Akt pathway. EGFR variant III (EGFRvIII) is a constitutively activated mutation of EGFR, that is, expressed in approximately 25% of GBM cases but not in normal tissues; Sonic Hedgehog (SHH), SHH is a secreted protein critical for pattern formation in the central nervous system. SHH ligand binding to its receptors, patched homolog (PTCH) and smoothened homolog (SMO), leads to the activation of gliotactin (GLI) transcription factors that are translocated into the nuclease to regulate various cellular activities, including the maintenance of cell stemness, survival, and proliferation; NOTCH, The Notch pathway is initiated by the binding of transmembrane ligands on one cell to the notch receptors on an adjacent cell. This binding causes the γ-secretase-mediated proteolytic release of the Notch intracellular domain (NICD). Released NICD translocates into the nucleus and then turns CSL (a transcriptional factor) from a repressor to an activator, causing various effects; WNT, Wnt signals are divided into 2 different pathways: the canonical or WNT/β-catenin pathway is involved in cell fate determination and the noncanonical pathway is involved in the control of cell movement and tissue polarity [35]. Following the binding of Wnt protein to a receptor complex comprising Frizzleds/low-density lipoprotein receptor-related protein (Fz/LRP), cytoplasmic disheveled (Dvl) is phosphorylated. The phosphorylation of Dvl inhibits the activity of glycogen synthase kinase-3β (GSK-3β), elevating nonphosphorylated β-catenin levels in the cytoplasm. β-Catenin translocates into the nucleus and forms a complex with members of the T-cell transcription factor (TCF)/lymphoid enhancer-binding factor (LEF) family of transcription factors.