Investigators

Summary

Glioblastomas are highly invasive primary tumors with poor prognosis despite current therapies. Individual targeted therapies have failed to offer long-term survival benefits, although combinations of rationally selected inhibitors may have significant therapeutic applicability for these tumors. Studies by our group and others have also shown aberrant, constitutive activation of NF-kB and Akt as common features of malignant gliomas, supporting their functional role in contributing to apoptosis resistance and refractory growth despite cytotoxic chemotherapy, irradiation, and molecularly targeted therapies. This activation may in part reflect deletions of NF-kB inhibitor-alpha, a common alteration in malignant gliomas, dysregulated stimulation by cell surface tyrosine kinases, such as EGFR and PDGFR-alpha, which are amplified in molecular subsets of malignant gliomas, and mutations in PTEN and other molecular targets that drive Akt and NF-kB activation. Thus, new therapeutic approaches are urgently needed. We have demonstrated that inhibition of NF-kB, Akt, and Bcl-2 may constitute a promising strategy to enhance the efficacy of conventional therapies, such as irradiation and cytotoxic chemotherapy, and potentiate the activity of agents targeted against growth signaling mediators.