Molecular targeted therapy in recurrent glioblastoma: current challenges and future directions.
BACKGROUND
The survival of patients with glioblastoma (GBM), which is the most common primary brain malignancy, remains poor with current treatment modalities. However, an enhanced understanding of gliomagenesis is supporting the development of targeted molecular therapies with the potential for improving clinical outcomes.


METHODS
Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) initiate key signaling pathways in GBM; however, trials with anti-EGFR agents have failed to show improved outcomes. Bevacizumab, a monoclonal antibody targeting VEGF, remains the only FDA-approved molecular drug in GBM; yet its use has only improved progression-free survival without any improvement in overall survival. We review the evidence supporting the continued evaluation of targeted molecular therapies in recurrent GBM. In addition, newer potential therapies targeting other signaling pathways, heat shock proteins and proteosomes, as well as the concept of targeting glioma stem cells are discussed.


CONCLUSIONS
The complex genetic origin of GBM makes it challenging to identify molecular subsets that may benefit from specific targeted therapies. Pathway inhibition, via multisite kinase inhibitors or a carefully selected combination of molecular drugs with or without cytotoxic agents, is currently undergoing evaluation in clinical trials and may improve outcomes in these patients.
Neuro-Oncology Outcomes, Neurological Institute, Cleveland Clinic, The Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland, OH, USA.
Mital
M
Patel
Michael A
MA
Vogelbaum
Gene H
GH
Barnett
Rakesh
R
Jalali
Manmeet S
MS
Ahluwalia
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology; D015195:Drug Design; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D058990:Molecular Targeted Therapy; D009364:Neoplasm Recurrence, Local; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013534:Survival
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors