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Gaspar N.,Institute of Cancer Research | Gaspar N.,Cancer Research UK Research Institute | Marshall L.,Institute of Cancer Research | Marshall L.,Cancer Research UK Research Institute | And 13 more authors.
Cancer Research | Year: 2010

Sensitivity to temozolomide is restricted to a subset of glioblastoma patients, with the major determinant of resistance being a lack of promoter methylation of the gene encoding the repair protein DNA methyltransferase MGMT, although other mechanisms are thought to be active. There are, however, limited preclinical data in model systems derived from pediatric glioma patients. We screened a series of cell lines for temozolomide efficacy in vitro, and investigated the differential mechanisms of resistance involved. In the majority of cell lines, a lack of MGMT promoter methylation and subsequent protein overexpression were linked to temozolomide resistance. An exception was the pediatric glioblastoma line KNS42. Expression profiling data revealed a coordinated upregulation of HOX gene expression in resistant lines, especially KNS42, which was reversed by phosphoinositide 3-kinase pathway inhibition. High levels of HOXA9/HOXA10 gene expression were associated with a shorter survival in pediatric high-grade glioma patient samples. Combination treatment in vitro of pathway inhibition and temozolomide resulted in a highly synergistic interaction in KNS42 cells. The resistance gene signature further included contiguous genes within the 12q13-q14 amplicon, including the Akt enhancer PIKE, significantly overexpressed in the KNS42 line. These cells were also highly enriched for CD133 and other stem cell markers. We have thus shown an in vitro link between phosphoinositide 3-kinase-mediated HOXA9/HOXA10 expression, and a drug-resistant, progenitor cell phenotype in MGMT-independent pediatric glioblastoma. ©2010 AACR. Source


Scanlan T.,A+ Network | Kaijage J.,Paediatric Oncology
British Journal of Haematology | Year: 2012

East Africa was at the forefront of early achievements and discoveries in paediatric oncology thanks to Denis Burkitt's seminal work. Although these successes have been built upon and continued elsewhere, they were sadly not sustained in sub-Saharan Africa for a variety of reasons. In recent years however this situation is slowly changing in countries across the continent. Tanzania is one such African country. Until very recently, survival rates of 5-10% for all children's cancers were expected. However, change has been brought about thanks to the combined efforts and commitments of the Tanzanian Ministry of Health, non-governmental organizations - such as The International Network for Cancer Treatment and Research and Children in Crossfire - and the participation of the private sector. Services are rapidly developing and outcomes are continuing to improve with 1-year survival rates of approximately 60% achieved. Efforts to maintain this early progress are concentrated around providing high quality local subspecialty medical training and continued local ownership of the programme. © 2012 Blackwell Publishing Ltd. Source


Ghafoor T.,Paediatric Haematology | Zaidi A.,Paediatric Oncology | Al Nassir I.,Shaukat Khanum Memorial Cancer Hospital and Research Center
Journal of the Pakistan Medical Association | Year: 2010

Granulocytic sarcoma is an extramedullary tumour of primitive granulocytic cells. It can develop at any anatomic site and is often a forerunner to the development of acute myelogenous leukaemia. Granulocytic sarcoma of the small intestine presents with abdominal pain and obstruction. We report a case of a 17-years-old boy who presented with epigastric pain. His endoscopy revealed multiple polypoid lesions throughout the duodenum and small bowel. Histopathology and flowcytometery confirmed the diagnosis of granulocytic sarcoma associated with acute myelogenous leukaemia. To our knowledge there have been only two previous case reports of multiple granulocytic sarcomas in the small intestine, both of these were adult patients. This is the first patient in the paediatric age group with multiple granulocytic sarcomas of the small intestine. Source


Bax D.A.,Institute of Cancer Research | Mackay A.,Institute of Cancer Research | Little S.E.,Institute of Cancer Research | Carvalho D.,Institute of Cancer Research | And 12 more authors.
Clinical Cancer Research | Year: 2010

Purpose: As genome-scale technologies begin to unravel the complexity of the equivalent tumors in adults, we can attempt detailed characterization of high-grade gliomas in children, that have until recently been lacking. Toward this end, we sought to validate and extend investigations of the differences between pediatric and adult tumors. Experimental Design: We carried out copy number profiling by array comparative genomic hybridization using a 32K bacterial artificial chromosome platform on 63 formalin-fixed paraffin-embedded cases of high-grade glioma arising in children and young people (<23 years). Results: The genomic profiles of these tumors could be subclassified into four categories: those with stable genomes, which were associated with a better prognosis; those with aneuploid and those with highly rearranged genomes; and those with an amplifier genotype, which had a significantly worse clinical outcome. Independent of this was a clear segregation of cases with 1q gain (more common in children) from those with concurrent 7 gain/10q loss (a defining feature of adults). Detailed mapping of all the amplification and deletion events revealed numerous low-frequency amplifications, including IGF1R, PDGFRB, PIK3CA, CDK6, CCND1, and CCNE1, and novel homozygous deletions encompassing unknown genes, including those at 5q35, 10q25, and 22q13. Despite this, aberrations targeting the "core signaling pathways" in adult glioblastomas are significantly underrepresented in the pediatric setting. Conclusions: These data highlight that although there are overlaps in the genomic events driving gliomagenesis of all ages, the pediatric disease harbors a distinct spectrum of copy number aberrations compared with adults. ©2010 AACR. Source


Bielen A.,Institute of Cancer Research | Perryman L.,Institute of Cancer Research | Box G.M.,Cancer Research UK Research Institute | Valenti M.,Cancer Research UK Research Institute | And 11 more authors.
Molecular Cancer Therapeutics | Year: 2011

Pediatric glioblastoma (pGBM), although rare, is one of the leading causes of cancer-related deaths in children, with tumors essentially refractory to existing treatments. We have identified IGF1R to be a potential therapeutic target in pGBM due to gene amplification and high levels of IGF2 expression in some tumor samples, as well as constitutive receptor activation in pGBM cell lines. To evaluate the therapeutic potential of strategies targeting the receptor, we have carried out in vitro and in vivo preclinical studies using the specific IGF1R inhibitor NVP-AEW541. A modest inhibitory effect was seen in vitro, with GI50 values of 5 to 6 mmol/L, and concurrent inhibition of receptor phosphorylation. Specific targeting of IGF1R with short interfering RNA decreased cell viability, diminished downstream signaling through phosphoinositide 3-kinase (PI3K), and induced G1 arrest, effects mimicked by NVP-AEW541, both in the absence and presence of IGF2. Hallmarks of PI3K inhibition were observed after treatment with NVP-AEW541 by expression profiling and Western blot analysis. Phospho-receptor tyrosine kinase (RTK) arrays showed phosphorylation of platelet-derived growth factor receptor (PDGFR) α/β in pGBM cells, suggesting coactivation of an alternative RTK pathway. Treatment of KNS42 with the PDGFR inhibitor imatinib showed additional effects targeting the mitogen-activated protein kinase pathway, and cotreatment of the PDGFR inhibitor imatinib with NVP-AEW541 resulted in a highly synergistic interaction in vitro and increased efficacy after 14 days therapy in vivo compared with either agent alone. These data provide evidence that inhibition of IGF1R, in combination with other targeted agents, may be a useful and novel therapeutic strategy in pGBM. ©2011 AACR. Source

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