Targeted Therapeutics in Patients With High-Grade Gliomas: Past, Present, and Future

摘要: 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, ATRX; codeletion chromosomes 1p 19q; DNA methylation; amplification genes such as epidermal growth factor receptor (EGFR) platelet-derived receptor, alpha polypeptide provides a more accurate prognostication biologic classification than classical histopathological diagnoses, number molecular markers being incorporated the new World Health Organization gliomas. However, improved understanding underlying alterations specific signaling pathways, these observations have so far failed to result successful application targeted has occurred other solid tumors. To date, only therapy for approved US Food Drug Administration is bevacizumab, targets vascular endothelial factor. EGFR remains dominant alteration represents potentially promising target, with drugs multiple types targeting development including vaccines, antibody drug conjugates, chimeric antigen (CAR) T cells, prior failures tyrosine kinase inhibitors. Immune therapies under investigation include checkpoint inhibitors, vaccines against tumor-associated antigens tumor-specific antigens, pulsed dendritic heat shock protein-tumor CAR cells. Mutations IDH1/2 central gliomagenesis proportion grade II III gliomas, ongoing trials examining IDH1, small inhibitors IDH1 IDH2, metabolic components NAD+ depletion target IDH-mutated The role methylation subset may be targetable, but better relation between epigenetic resulting tumor biology appears necessary. Ultimately, given failure single-agent high-grade it that novel combinatorial or immunomodulatory approaches will likely necessary successfully combat challenging