Molecular targeting of glioblastoma: Drug discovery and therapies

Abstract

Despite advances in treatment for glioblastoma multiforme (GBM), patient prognosis remains poor. Although there is growing evidence that molecular targeting could translate into better survival for GBM, current clinical data show limited impact on survival. Recent progress in GBM genomics implicate several activated pathways and numerous mutated genes. This molecular diversity can partially explain therapeutic resistance and several approaches have been postulated to target molecular changes. Furthermore, most drugs are unable to reach effective concentrations within the tumor owing to elevated intratumoral pressure, restrictive vasculature and other limiting factors. Here, we describe the preclinical and clinical developments in treatment strategies of GBM. We review the current clinical trials for GBM and discuss the challenges and future directions of targeted therapies.

Figure 1

Schematic overview of current molecular targeted therapies of GBM. Aberrant oncogenic RTK pathways are frequent therapeutic targets in GBM. The PI3K-Akt (green) and RAS (pink) oncogenic pathways are often targeted intracellularly with small molecules inhibitors. EGF, VEGF and PDGF as well as their receptors can be blocked by small molecules and monoclonal antibodies. Items in blue boxes include examples of drugs targeting on the respective pathways. Abbreviations: ECM: extracellular matrix, MMP: matrix metalloproteinase, Topo I: topoisomerase I.

Figure 2

Histological features of human GBMs. Paraffin-embeded human GBM samples were stained with H&E. Human GBMs are characterized by pseudopalisading necrosis (N) in a garlandlike arrangement of hypercellular tumor nuclei (pseudopalisades: green arrows) lining up around tumor necrosis (N) containing pyknotic nuclei (black arrowheads). Further features include hemorrhage (H) and multi-nucleated giant cells (yellow arrows).

Figure 3

Histological features of select rodent GBMs. (a) GL261, (b) 060919 and (c) F98 tumors were grown in the frontal lobe of C57BL6 mouse, athymic nude rat or F344 Fischer rat, respectively. Paraffin-embedded brain samples were stained with H&E. In 060919, the pseudopalisading necrosis is especially pronounced and histological features of necrosis, giant cells, hemorrhage and invasive growth closely resemble those in human GBM. Abbreviations: T: tumor, B: brain, N: necrosis, H: hemorrhage. Symbols: yellow arrow: invasion, red arrow: giant cell, green arrow: pseudopalisades.