Targeted Brain Tumor Treatment: Current Perspectives

Ningaraj N.S1, Salimath B.P2, Sankpal U.T1, Perera R1 and Vats T1

1Department of Pediatric Neurooncology and Molecular Pharmacology, Hoskins Center, Curtis and Elizabeth Anderson Cancer Institute, Memorial Health University Medical Center, Mercer University Medical School, 4700 Waters Avenue, Savannah, GA 31404, U.S.A. 2Department of Biotechnology, University of Mysore, Mysore 570006, Karnataka, India.

Abstract:

Brain tumor is associated with poor prognosis. The treatment option is severely limited for a patient with brain tumor, despite great advances in understanding the etiology and molecular biology of brain tumors that have lead to breakthroughs in developing pharmaceutical strategies, and ongoing NCI/Pharma-sponsored clinical trials. We reviewed the literature on molecular targeted agents in preclinical and clinical studies in brain tumor for the past decade, and observed that the molecular targeting in brain tumors is complex. This is because no single gene or protein can be affected by single molecular agent, requiring the use of combination molecular therapy with cytotoxic agents. In this review, we briefly discuss the potential molecular targets, and the challenges of targeted brain tumor treatment. For example, glial tumors are associated with over-expression of calcium-dependent potassium (KCa) channels, and high grade glioma express specific KCa channel gene (gBK) splice variants, and mutant epidermal growth factor receptors (EGFRvIII). These specific genes are promising targets for molecular targeted treatment in brain tumors. In addition, drugs like Avastin and Gleevec target the molecular targets such as vascular endothelial cell growth factor receptor, platelet-derived growth factor receptors, and BRC-ABL/Akt. Recent discovery of non-coding RNA, specifically microRNAs could be used as potential targeted drugs. Finally, we discuss the role of anti-cancer drug delivery to brain tumors by breaching the blood-brain tumor barrier. This non-invasive strategy is particularly useful as novel molecules and humanized monoclonal antibodies that target receptor tyrosine kinase receptors are rapidly being developed.

Abbreviations:

BBB: blood-brain barrier; BTB: blood-tumor barrier; KCa: calcium-dependent potassium channels; NS-1619/NS 004: 1,3-dihydro-1-5-(trifl uoromethyl)-2H benzimidazol-2-one; HBMVEC: human brain microvascular endothelial cells; FACS: fluorescence activated cell sorting; PDGFR: platelet-derived growth factor receptor; RTKIs: receptor tyrosine kinase inhibitors; EGFR: epidermal growth factor receptor; EGFRvIII: variant III of the human EGFR; gBK channel: glioma specific spice variant of KCa channel gene; KATP: ATP sensitive potassium channels; Minoxidil sulfate (MS: KATP channel agonist);Trastuzumab (Herceptin, Her-2 inhibitor, Genentech Inc.).