Editors' ChoiceCancer

Toward the Future of Personalized Medicine

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Science Translational Medicine  02 Mar 2011:
Vol. 3, Issue 72, pp. 72ec28
DOI: 10.1126/scitranslmed.3002294

Perhaps no disease is better suited than glioblastoma multiforme (GBM)—one of the most common and deadly brain tumors—for illustrating the concept of personalized medicine. Previous studies have shown that either amplification or activating mutations of the epidermal growth factor receptor (EGFR) gene occur in 30 to 50% of GBM cases, with the majority of the remaining cases displaying evidence of EGFR pathway hyperactivation. Despite these findings, molecular therapies targeting EGFR have not been shown to be clinically effective, presumably because of cross-coupled signaling from other growth factors.

In order to identify downstream molecular targets of the EGFR pathway, Bredel and colleagues used a powerful multidimensional genomic analysis to study 10 sets of GBM patients whose tissue samples and treatment information were available. Surprisingly, they found that deletion of NFKBIA, an inhibitor of the EGFR signaling pathway, was common in GBM (20 to 30%), particularly in nonclassical subtypes. Interestingly, there appeared to be a mutually exclusive pattern of NFKBIA deletion and EGFR amplification. Together, alterations in these two genes accounted for more than half of all of the GBM cases analyzed. These data suggest that NFKBIA is a downstream effector of the EGFR signaling pathway. Lastly, restoration of NFKBIA expression in primary GBM and established cell lines inhibited tumor growth, triggered apoptosis, and rendered these tumors more sensitive to temozolomide. This supports a role for NFKBIA as a tumor suppressor gene in GBM.

NFKBIA gene expression correlated independently with survival. More importantly, when combined with O6-methylguanine DNA methyl-transferase (MGMT) status—the only other known predictor of temozolomide response in GBM—there was a strong association between risk status and survival, with an estimated median survival in the low-risk (high NFKBIA/low MGMT), intermediate-risk (low NFKBIA/low MGMT or high NFKBIA/high MGMT), and high-risk (low NFKBIA/high MGMT) groups of 92, 59, and 44 weeks, respectively. These impressive results firmly establish the tumor suppressor function of NFKBIA and its prognostic utility regarding GBM. Although the detailed molecular network connecting EGFR and NFKBIA has yet to emerge, the identification of the molecular signature, in combination with MGMT status, may help to prognosticate GBM, to preselect patients for treatments, and to test previously unidentified, molecularly targeted compounds, such as NF-κB inhibitors. The best is still yet to come for NFKBIA.

M. Bredel et al., NFKBIA deletion in glioblastoma. N. Engl. J. Med. 364, 627–637 (2011). [Abstract]

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