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infi ltrating, high-grade malignant glioma phenotype with prominent pathological
and molecular resemblance to GBM in humans (Zhu et al. 2009 ). Studies of the
activation of signaling events in these GBM tumor cells revealed notable differences
between wild-type and vIII EGFR-expressing cells. Whereas wild-type EGF recep-
tor signals through its canonical pathways, tumors arising from expression of mutant
EGFRvIII do not use these same pathways. These fi ndings provide critical insights
into the role of mutant EGFR signaling function in GBM tumor biology and set the
stage for testing of targeted therapeutic agents in suitable preclinical models.
A comprehensive analysis using next-generation sequencing technologies has
led to the discovery of a variety of genes that were not known to be altered in GBMs
(Parsons et al. 2008 ). There were recurrent mutations in the active site of isocitrate
dehydrogenase 1 (IDH1) in 12 % of GBM patients; these occurred in a large frac-
tion of young patients and in most patients with secondary GBMs and were associ-
ated with an increase in overall survival. These studies demonstrate the value of
unbiased genomic analyses in the characterization of human brain cancer and iden-
tify a potentially useful genetic alteration for the classifi cation and targeted therapy
of GBMs.
Nuclear factor-kappaB (NF-κB) activation may play an important role in the
pathogenesis of cancer and also in resistance to treatment. Inactivation of the p53
tumor suppressor is a key component of the multistep evolution of most cancers.
Links between the NF-κB and p53 pathways are under intense investigation.
Receptor interacting protein 1 (RIP1), a central component of the NF-κB signaling
network, negatively regulates p53 tumor suppressor signaling (Park et al. 2009b ).
Loss of RIP1 from cells results in augmented induction of p53 in response to DNA
damage, whereas increased RIP1 level leads to a complete shutdown of DNA
damage- induced p53 induction by enhancing levels of cellular mdm2. The key
signal generated by RIP1 to up-regulate mdm2 and inhibit p53 is activation of
NF-κB. The clinical implication of this fi nding is shown in GBM, where RIP1 is
commonly overexpressed, but not in grades II and III glioma. RIP1 activates
NF-κB and then that increases the expression of the gene mdm2, which inhibits
the p53 gene in GBM. Increased expression of RIP1 confers a worse prognosis.
These results show a key interaction between the NF-κB and p53 pathways that
may have implications for the targeted treatment of GBM. One of the next steps is
to determine whether these patients may respond better to drugs targeting the
NF-κB network.
Glioma Actively Personalized Vaccine Consortium
A research consortium, Glioma Actively Personalized Vaccine Consortium
(GAPVAC), consisting of 14 partners from 7 European countries plus the US was
formed in 2013 ( http://gapvac.eu/ ). Led by Immatics Biotechnologies, and sup-
ported by the EU with a grant through its 7th Framework Program, GAPVAC
announced plans to develop a personalized brain tumor therapy. The GAPVAC proj-
ect is designed to create, manufacture and develop actively personalized vaccines
10 Personalized Therapy of Cancer