title: Targeted Therapeutics in Patients With High-Grade Gliomas: Past, Present, and Future.
abstract: High-grade gliomas remain incurable despite current therapies, which are plagued by high morbidity and mortality. Molecular categorization of glioma subtypes using mutations in isocitrate dehydrogenase 1/2 (IDH1/2), TP53, and ATRX; codeletion of chromosomes 1p and 19q; DNA methylation; and amplification of genes such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor, alpha polypeptide provides a more accurate prognostication and biologic classification than classical histopathological diagnoses, and a number of molecular markers are being incorporated in the new World Health Organization classification of gliomas. However, despite the improved understanding of the molecular subtypes of gliomas and the underlying alterations in specific signaling pathways, these observations have so far failed to result in the successful application of targeted therapies, as has occurred in other solid tumors. To date, the only targeted therapy for gliomas approved by the US Food and Drug Administration is bevacizumab, which targets vascular endothelial growth factor. EGFR remains a dominant molecular alteration in specific glioma subtypes and represents a potentially promising target, with drugs of multiple types targeting EGFR in development including vaccines, antibody drug conjugates, and chimeric antigen receptor (CAR) T cells, despite the prior failures of EGFR tyrosine kinase inhibitors. Immune therapies under investigation include checkpoint inhibitors, vaccines against tumor-associated antigens and tumor-specific antigens, pulsed dendritic cells, heat shock protein-tumor conjugates, and CAR T cells. Mutations in the IDH1/2 genes are central to gliomagenesis in a high proportion of grade II and III gliomas, and ongoing trials are examining vaccines against IDH1, small molecular inhibitors of IDH1 and IDH2, and metabolic components including NAD+ depletion to target IDH-mutated gliomas. The central role of DNA methylation in a subset of gliomas may be targetable, but better understanding of the relation between epigenetic alterations and resulting tumor biology appears necessary. Ultimately, given the prior failure of single-agent targeted therapy in high-grade gliomas, it appears that novel combinatorial therapy or targeted drugs with immunomodulatory or epigenetic approaches will likely be necessary to successfully combat these challenging tumors.
authors.affiliation: Department of Neurology, Clinical Neurosciences Center, University of Utah, Salt Lake City, UT, USA.
authors.forename: Ricky
authors.initials: R
authors.lastname: Chen
authors.affiliation: Division of Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: Adam L
authors.initials: AL
authors.lastname: Cohen
authors.affiliation: Department of Neurosurgery, Huntsman Cancer Institute and Clinical Neuroscience Center, University of Utah, 175 N. Medical Drive East, Salt Lake City, UT, 84132, USA. neuropub@hsc.utah.edu.
authors.forename: Howard
authors.initials: H
authors.lastname: Colman
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality / Q000473:pathology*; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D060787:Neoplasm Grading; D011379:Prognosis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor
keywords: Brain tumor; Glioblastoma; Glioma; Targeted therapies