NF-κB and STAT3 in glioblastoma: therapeutic targets coming of age

Abstract

Since we last addressed the roles of NF-κB and JAK/STAT3 signaling in glioblastoma (GBM) 5 years ago, tremendous strides have been made in the understanding of these two pathways in glioma biology. Contributing to prosurvival mechanisms, cancer stem cell maintenance and treatment resistance, both NF-κB and STAT3 have been characterized as major drivers of GBM. In this review, we address general improvements in the molecular understanding of GBM, the structure of NF-κB and STAT3 signaling, the ways in which these pathways contribute to GBM and advances in preclinical and clinical targeting of these two signaling cascades.

Keywords::

• glioblastoma
• neurotherapeutics
• NF-κB
• signaling
• STAT3

Acknowledgements

The authors would like to acknowledge GP Meares for critical review of the figures.

Financial & competing interests disclosure

Funding for this work was provided by grants from the National Institutes of Health (R01CA138517 to S.E.N. and R01NS057563 and R01NS050665 to E.N.B.); American Brain Tumor Association Basic Research Fellowship in Honor of Paul Fabbri (B.C.M.); William E. Cash Jr. Memorial Fund in Neuro-Oncology Research (B.C.M and S.E.N.) and the UAB Comprehensive Cancer Center (S.E.N.). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Glioblastoma (GBM) is the most aggressive and malignant tumor of the CNS and remains essentially incurable.

• The Cancer Genome Atlas and additional groups have determined that GBM tumor can be characterized genetically into four molecular subtypes.

• Recently, studies have discovered that each patient’s tumor can harbor more than one molecular subtype, highlighting the complex heterogeneity in GBM.

• Both NF-κB and STAT3 have been linked to GBM grade, the Mesenchymal molecular subtype, stem cell maintenance and resistance to therapies.

• Multiple mechanisms of crosstalk between the NF-κB and STAT3 pathways have been discovered, revealing a vicious signaling cycle that occurs in GBM.

• Clinical trials testing NF-κB and STAT3 inhibition are in progress, and although in their infancy, will soon provide answers to the questions regarding efficacy in patients with GBM.

• Personalized therapies targeting the molecular subtype(s) in combination with additional approaches including immunotherapy are the future of GBM clinical research.