Abstracts from the 2011 BNOS Conference, June 29 – July 1, 2011, Homerton College, Cambridge
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INTRODUCTION: Tumour suppressor merlin deficiency leads to the development of schwannomas, meningiomas and ependymomas. Using our in vitro model of human schwannoma we have demonstrated that merlin-deficiency leads to increased cell proliferation, cell-matrix adhesion and survival involving ErbB2/3, platelet-derived-growth-factor-receptor-β (PDGFR-β), and Insulin-like growth factor receptor-I (IGF-IR) acting via extracellular-signal-regulated-kinase 1/2 (ERK1/2), AKT and JNK. We have inhibited increased proliferation of schwannoma by AZD6244, sorafenib 2, nilotinib, lapatinib 1 and BEZ-235. Since, schwannoma overexpress multiple receptors/signalling pathways the inhibition of a single target is not sufficient. Therefore, all relevant receptors/signalling pathways must be revealed. AXL subfamily RTKs (AXL, SKY, MER and Ron) are over-expressed in cancers correlating with poor prognosis. Expression profiling and phosphoprotein arrays showed that Axl-family receptors are overexpressed/activated in human schwannoma. METHODS: Western blotting, immunohistochemistry, primary human cell culture, proliferation/adhesion assays. RESULTS: AXL, SKY and their ligand Gas-6 are over-expressed as well as activated in human schwannoma cells and tissues leading to increased proliferation and adhesion. CONCLUSIONS: Axl, SKY and Gas-6 constitute new potential therapeutic targets in merlin- deficient tumours. INTRODUCTION: Paediatric ependymomas remain a clinical challenge with a relatively poor prognosis. An improved understanding of ependymoma biology may identify new correlates of outcome and potential therapeutic targets. METHODS: Affymetrix 500K SNP arrays were used to identify genomic imbalances in 42 primary and 21 recurrent paediatric ependymomas. Selected gene copy number alterations were validated by quantitative real-time polymerase chain reaction (qPCR). Candidates from the SNP analysis were incorporated into a panel of putative prognostic markers assessed by FISH and immunohistochemistry across a tissue microarray cohort of 107 primary ependymomas treated according to two age defined paediatric clinical trials (CCLG 1992 04 and SIOP 1999 04). RESULTS: Chromosome 1q gain was the most common anomaly in primary and recurrent intracranial ependymomas, while tumours from different locations harboured characteristic aberrations. Unsupervised hierarchical clustering of cytoband anomalies identified a sample group characterised by chromosome 1q21.3 gain which demonstrated a worse five year event-free survival (0 v 56.1%; univariate analysis p = 0.003, multivariate cox regression analysis p = 0.02). Within this region, gain of PRUNE was associated with a reduced five year overall survival when assessed across the primary cohort (65.6 v 88.1%; p = 0.025, multivariate p = 0.045). Immunohistochemistry identified PRUNE overexpression as an independent marker of reduced event-free and overall survival in infant intracranial ependymomas (multivariate p = 0.007). It was also associated with reduced overall survival in older children (univariate p = 0.02). CONCLUSION: This study identifies PRUNE as the first prognostic correlate in uniformly treated paediatric intracranial ependymomas. Confirmation in an independent European infant trial could result in the incorporation of PRUNE into future trial decisions regarding therapeutic stratification of children with this tumour. INTRODUCTION: Paediatric high grade gliomas (pHGG) remain tumours with a poor prognosis for which novel therapeutic strategies are needed. Poly (ADP-ribose) polymerase (PARP) is known to have multiple functions in tumours including single strand DNA repair and induction of caspase independent apoptosis. It has been suggested as a therapeutic target in adult malignancies and this study examines whether it could be a potential target in pHGG. METHODS: Tissue microarrays containing 150 formalin fixed pHGG were examined by immunohistochemistry for levels of PARP and apoptosis inducing factor (AIF) expression. Full retrospective clinical data were also available for this cohort and statistical analysis was performed to assess for the effect of PARP status on prognosis. Copy number of 1q was assessed by array comparative genomic hybridisation and fluorescent in situ hybridisation. RESULTS: Level of PARP immunopositivity had a statistically significant positive correlation with survival in supratentorial paediatric high grade glioma. AIF staining was notable for its absence in the majority of tumours but with higher levels of expression in non-neoplastic brain. Extent of surgical resection and administration of chemotherapy or radiotherapy were the other significant factors on multi-variate analysis. No correlation was found between gain of 1q and PARP immunopositivity levels. CONCLUSIONS: PARP is expressed at significant levels in many pHGG and has a significant correlation with prognosis, though this increased expression is not DNA copy number driven. In these tumours the ability of PARP to activate AIF appears to have been lost. PARP may therefore represent a promising therapeutic target for these lesions.
