Abstract A19: Role of NF-κB and gene targets of NF-κB in glioma cell plasticity

Glioblastoma (GBM) is the most common and lethal form of intracranial tumor. In the last century we have accumulated tremendous amounts of data on this type of cancer, but despite extensive study, few therapeutic targets have been identified for GBM. We have established a lentiviral-induced mouse model of malignant gliomas, which faithfully captures the pathophysiology and molecular signatures of human GBM. RNAseq analysis of these tumors revealed high NFκB activation showing enrichment of known NFκB target genes. Depletion of IKK2 in tumor derived cell lines attenuated tumor proliferation and prolonged mouse survival. We have previously shown that gliomas can originate by reprograming/dedifferentiation of terminally differentiated astrocytes and neurons following oncogenic insult. This tumor cell plasticity seems to be impaired when either cortical astrocytes or neurons derived from floxed-IKK2 mice are infected with a lentivirus expressing HRAS-iresCREerT2-shp53. The addition of tamoxifen to the infected cells induces IKK2 depletion and blocks the reprogramming process, manifested by inhibition of tumorspheres formation and retention of differentiation makers. When these cells are transplanted into mice, the control group (vehicle treated) succumbs to the disease, while induction of IKK2 depletion in the tamoxifen treated group (20 days post-transplantation) significantly prolonged the mice survival. Activation of NFκB requires the activity of IκB kinase (IKK) complex containing IKKα and IKKβ, and the regulatory protein NFκB essential modifier (NEMO). We tested a peptide corresponding to the NEMO-binding domain (NBD) of IKKα(IKK1) or IKKβ(IKK2), to specifically inhibit the induction of NFκB activation, and the mice treated with NBDwt peptide showed long-term survival compared to NBDmut control. We propose targeting the NFκB pathway as an attractive therapeutic strategy to treat GBM. Citation Format: Dinorah Friedmann-Morvinski, Rajesh Narasimamurthy, Yifeng Xia, Chad Myskiw, Yasushi Soda, Inder M. Verma. Role of NF-κB and gene targets of NF-κB in glioma cell plasticity. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr A19.