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

  • Neuro-oncology (GJ Lesser, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

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.

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Abbreviations

ATRX:

Alpha thalassemia/mental retardation syndrome X-linked

CDKN2A/B:

Cyclin-dependent kinase inhibitor 2A or 2B

CIC:

Capicua transcriptional repressor

DAXX:

Death domain-associated protein

Epha2:

Ephrin type-A receptor 2 precursor

FUBP1:

Far upstream element binding protein 1

H3F3A:

H3 histone, family 3A

IL-13Ra2:

Interleukin 13 receptor subunit alpha 2

MGMT:

0-6-methylguanine-DNA methyltransferase

MTOR:

Mechanistic target of rapamycin

NF-kB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

PARP:

Poly ADP ribose polymerase

PIK3CA:

Phosphatidylinositol-4,5-bisphosphonate 3-kinase, catalytic subunit alpha

PTEN:

Phosphatase and tensin homolog

RB1:

Retinoblastoma 1 gene

STAT3:

Signal transducer and activator of transcription 3

TERT:

Telomerase reverse transcriptase

TP53:

Tumor protein 53

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Acknowledgments

We thank Kristin Kraus, M.Sc., for editorial assistance in preparing this paper.

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Authors and Affiliations

  1. Department of Neurology, Clinical Neurosciences Center, University of Utah, Salt Lake City, UT, USA

    Ricky Chen MD

  2. Division of Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

    Adam L. Cohen MD

  3. Department of Neurosurgery, Huntsman Cancer Institute and Clinical Neuroscience Center, University of Utah, 175 N. Medical Drive East, Salt Lake City, UT, 84132, USA

    Howard Colman MD, PhD

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  1. Ricky Chen MD
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Correspondence to Howard Colman MD, PhD.

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Conflict of Interest

Ricky Chen declares that he has no conflict of interest.

Adam L. Cohen declares that he has no conflict of interest.

Howard Colman is the site PI for clinical trials (institutional contract) conducted with Plexxikon and NewLink Genetics and has received compensation from Roche, Genentech, Upsher-Smith, Oxigene, CytRx, Novocure, and Omniox for service on advisory boards.

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Chen, R., Cohen, A.L. & Colman, H. Targeted Therapeutics in Patients With High-Grade Gliomas: Past, Present, and Future. Curr. Treat. Options in Oncol. 17, 42 (2016). https://doi.org/10.1007/s11864-016-0418-0

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