Small-Molecule Inhibitors in Glioblastoma: Key Pathways and Resistance Mechanisms

Abstract

Glioblastoma, the most common and aggressive form of primary adult brain tumor, is a devastating disease with a dismal two-year survival. Attempts to improve patient survival include a variety of treatment options, from monoclonal antibodies, vaccines, and microbubbles to exosomes and small-molecule inhibitors, all of which are in various stages of preclinical and clinical development. The most frequently tested type of novel therapeutics are the small-molecule inhibitors targeting key signaling pathways dysregulated in GBM, including TP53, retinoblastoma, and the receptor tyrosine kinase-driven EGF, PDGF, and c-MET pathways. This chapter will compare preclinical and clinical results for a subset of inhibitors targeting the receptor tyrosine kinase families EGF, VEGF, and PDGF along with the PI3K/Akt/mTor pathway and cell cycle inhibitors. In the discussion, potential resistance mechanisms which continue to pose significant barriers to effective small-molecule inhibition treatment of GBM will be discussed along with possible improvements.