Nottingham, United Kingdom
Nottingham, United Kingdom

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Levesley J.,Childrens Brain Tumour Research Center | Lusher M.E.,Newcastle University | Lindsey J.C.,Newcastle University | Clifford S.C.,Newcastle University | And 2 more authors.
Neuro-Oncology | Year: 2011

The RASSF1A tumor suppressor is potentially the most important candidate gene identified in medulloblastoma to date, being epigenetically silenced in >79% of primary tumors. However, its functional role has not been previously addressed in this tumor type. Here, we demonstrate that expression of RASSF1A promotes the induction of cell death after activation of both the extrinsic and intrinsic apoptotic pathways in medulloblastoma cells. Treatment of UW228-3 cells stably expressing RASSF1A with an anti-CD95 antibody to induce extrinsic apoptosis and etoposide or cisplatin to activate intrinsic apoptosis augmented tumor cell killing in a caspasedependent manner. This led to increased activation of the pro-apoptotic BCL-2 family member BAX. On the basis of this knowledge, we demonstrate how the loss of RASSF1A function in medulloblastoma cells might be overcome using the novel BH3-only mimetic ABT-737 in combination with chemotherapeutic agents to target the BCL-2 anti-apoptotic members. We show that ABT-737 increased susceptibility to apoptosis induced by DNA damage regardless of RASSF1A expression status through increased activation of BAX. Our findings identify the RASSF1A tumor suppressor as a promoter of apoptotic signaling pathways. Investigation of its mechanism of action has revealed that these pathways can still be promoted in its absence and how these potentially represent novel therapeutic targets for medulloblastoma. © The Author(s) 2011.

Bouffet E.,University of Toronto | Taylor R.E.,Singleton Hospital | Hargrave D.,Royal Marsden Hospital | Walker D.,Childrens Brain Tumour Research Center | And 4 more authors.
Journal of Neuro-Oncology | Year: 2010

The study aimed to examine the tolerability of the combination of radiotherapy and tamoxifen and the effect on median and event free survival as well as collecting data on the use of steroids in this population. 31 patients with diffuse intrinsic pontine glioma, diagnosed on clinical and radiological criteria, were treated with high-dose oral tamoxifen (120 mg/m2/day) given concomitantly with standard dose radiotherapy (54 Gy in 1.8 Gy fractions over 6 weeks). Results: Tamoxifen was well tolerated with no grade 3 or 4 CTC toxicity reported. At 1 year, the progression free and event free survival were 3.2% (95% CI: 0.2-14.1%), and at 6 months 19.4% (CI: 7.9% to 34.6%). The overall survival at 1 year was 16.1% (CI: 5.9-30.9%) with median survival 6.32 months. In this study, in which tamoxifen was used in conjunction with radiotherapy, progression free survival was shown to be less good when compared with historical data HR = 3.1 (CI: 1.7-5.7). There was no significant reduction in overall survival. The addition of high-dose tamoxifen, although well tolerated, confers no clinical benefit to patients treated with diffuse intrinsic pontine glioma treated with standard radiotherapy. © 2010 UK Crown.

Henriquez N.V.,University College London | Forshew T.,Queen Mary, University of London | Forshew T.,University of Cambridge | Tatevossian R.,Queen Mary, University of London | And 10 more authors.
Cancer Research | Year: 2013

Brain tumors are thought to originate from stem/progenitor cell populations that acquire specific genetic mutations. Although current preclinical models have relevance to human pathogenesis, most do not recapitulate the histogenesis of the human disease. Recently, a large series of human gliomas and medulloblastomas were analyzed for genetic signatures of prognosis and therapeutic response. Using a mouse model system that generates three distinct types of intrinsic brain tumors, we correlated RNA and protein expression levels with human brain tumors. A combination of genetic mutations and cellular environment during tumor propagation defined the incidence and phenotype of intrinsic murine tumors. Importantly, in vitro passage of cancer stem cells uniformly promoted a glial expression profile in culture and in brain tumors. Gene expression profiling revealed that experimental gliomas corresponded to distinct subclasses of human glioblastoma, whereas experimental supratentorial primitive neuroectodermal tumors (sPNET) correspond to atypical teratoid/ rhabdoid tumor (AT/RT), a rare childhood tumor. © 2013 American Association for Cancer Research.

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