Targeting NF-kappa B in glioblastoma: A therapeutic approach

Glioblastoma multiforme (GBM) is the most common and lethal form of intracranial tumor. We have established a lentivirus-induced mouse model of malignant gliomas, which faithfully captures the pathophysiology and molecular signature of mesenchymal human GBM. RNA-Seq analysis of these tumors revealed high nuclear factor kappa B (NF-kappa B) activation showing enrichment of known NF-kappa B target genes. Inhibition of NF-kappa B by either depletion of I kappa B kinase 2 (IKK2), expression of a I kappa BaM super repressor, or using a NEMO (NF-kappa B essential modifier)-binding domain (NBD) peptide in tumor-derived cell lines attenuated tumor proliferation and prolonged mouse survival. Timp1, one of the NF-kappa B target genes significantly up-regulated in GBM, was identified to play a role in tumor proliferation and growth. Inhibition of NF-kappa B activity or silencing of Timp1 resulted in slower tumor growth in both mouse and human GBM models. Our results suggest that inhibition of NF-kappa B activity or targeting of inducible NF-kappa B genes is an attractive therapeutic approach for GBM.