Pilocytic astrocytoma (PA) is the most common glioma of childhood. Despite their relatively high incidence, the molecular mechanisms responsible for tumorigenesis and growth of PA are poorly understood. Previous in vitro studies in our laboratory showed that despite the absence of ErbB1, PA was sensitive to ErbB1 tyrosine kinase inhibitor gefitinib. To identify alternative targets of gefitinib in PA, we studied other members of the ErbB receptor tyrosine kinase family that have been identified in brain tumors. Using gene expression microarray and Western blot analyses, we found that ErbB3 is highly overexpressed in PA compared with other pediatric brain tumors (glioblastoma, ependymoma, medulloblastoma, atypical teratoid/rhabdoid tumor, and choroid plexus papilloma). Developmental biology studies have identified Sox10 as a regulator of ErbB3 expression during development of the neural crest. Investigation of Sox10 in PA revealed that it is highly overexpressed relative to other pediatric brain tumors, lending support to the theory that Sox10-regulated overexpression of ErbB3 may be driving growth in PA. Sox10-regulated ErbB3 overexpression is a novel insight into the biology of PA, suggests possible recapitulation of developmental pathways in tumorigenesis, and presents possible targets for therapeutic intervention that might be used for hypothalamic variants not amenable to surgical cure.
Ependymomas account for 6-12% of all pediatric intracranial tumors. Despite complete resection and radiation, about 50% of patients relapse and have subsequent dismal prognoses. As no clinical findings reliably forecast tumor recurrence, we sought to determine if gene expression profiling could be used to distinguish patients at high risk for relapse at initial diagnosis, and thereby make them candidates for innovative treatments at an early stage. We extracted RNA from 13 ependymoma specimens: 7 from patients who experienced tumor recurrence, and 6 from patients who have not recurred. RNA was applied to Affymetrix HG-U133 plus 2.0 microarray chips, and microarrays were analyzed with GeneSpring 7.0 and Prediction Analysis of Microarrays (PAM) software. The 3-gene subset of PLEK (pleckstrin), NF-kappaB2 (nuclear factor kappa beta-2), and LOC374491 (TPTE and PTEN homologous inositol phosphatase pseudogene) was identified as the minimal subset capable of accurately distinguishing tumors according to recurrence. In summary, gene expression profiling may be valuable, perhaps in combination with clinical findings identified in some studies, for identifying children at high risk for ependymoma relapse.
Based on these preclinical data, gefitinib may be a suitable salvage chemotherapy drug to explore further in those patients with JPA who have recurred after primary chemotherapy. Of interest, it appears that the anti-tumor effect of gefitinib in JPA cell-cultures may be mediated through a pathway other than EGFR inhibition.
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