A Critical Overview of Targeted Therapies for Glioblastoma

Abstract

Over the past century, treatment of malignant tumors of the brain has remained a challenge. Refinements in neurosurgical techniques, discovery of powerful chemotherapeutic agents, advances in radiotherapy, applications of biotechnology, and improvements in methods of targeted delivery have led to some extension of length of survival of glioblastoma patients. Refinements in surgery are mentioned because most of the patients with glioblastoma undergo surgery and many of the other innovative therapies are combined with surgery. However, cure of glioblastoma has remained elusive because it requires complete destruction of the tumor. Radical surgical ablation is not possible in the brain and even a small residual tumor leads to rapid recurrence that eventually kills the patient. Blood-brain barrier (BBB) comprising brain endothelial cells lining the cerebral microvasculature, limits delivery of drugs to the brain. Even though opening of the BBB in tumor core occurs locally, BBB limits systemic chemotherapy especially at the tumor periphery, where tumor cells invade normal brain structure comprising intact BBB. Comprehensive approaches are necessary to gain maximally from promising targeted therapies. Common methods used for critical evaluation of targeted therapies for glioblastoma include: (1) novel methods for targeted delivery of chemotherapy; (2) strategies for delivery through BBB and blood-tumor barriers; (3) innovations in radiotherapy for selective destruction of tumor; (4) techniques for local destruction of tumor; (5) tumor growth inhibitors; (6) immunotherapy; and (7) cell/gene therapies. Suggestions for improvements in glioblastoma therapy include: (1) controlled targeted delivery of anticancer therapy to glioblastoma through the BBB using nanoparticles and monoclonal antibodies; (2) direct introduction of genetically modified bacteria that selectively destroy cancer cells but spare the normal brain into the remaining tumor after resection; (3) use of better animal models for preclinical testing; and (4) personalized/precision medicine approaches to therapy in clinical trials and translation into practice of neurosurgery and neurooncology. Advances in these techniques suggest optimism for the future management of glioblastoma.

Keywords: brain cancer; cancer immunotherapy; gene therapy; glioblastoma; malignant glioma; oncolysis; personalized therapy; targeted delivery.

Figure 1

A concept of targeted drug delivery to glioblastoma across the BBB. Nanoparticle (N) combined with a monoclonal antibody (MAb) for receptor (R) crosses the blood brain barrier (BBB) into brain by Trojan horse approach. N with a ligand targeting BBB traverses the BBB by receptor-mediated transcytosis. Ligand ▸ docks on a cancer cell receptor N⊳ and delivers anticancer payload to the cancer cell in glioblastoma.