FANCD2 re-expression is associated with glioma grade and chemical inhibition of the Fanconi Anaemia pathway sensitises gliomas to chemotherapeutic agents
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Abhijit A. Patil1, Parag Sayal2, Marie-Lise Depondt1, Ryan D. Beveridge1, Anthony Roylance2, Deepti H. Kriplani1, Katie N. Myers1, Angela Cox1, David Jellinek2, Malee Fernando3, Thomas A. Carroll2 and Spencer J. Collis1
1 Sheffield Cancer Research Centre, Academic Unit of Molecular Oncology, Department of Oncology, University of Sheffield Medical School, Beech Hill Road, Sheffield, UK
2 Neuro-Oncology Group, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield, UK
3 Department of Histopathology, Sheffield Teaching Hospitals, Royal Hallamshire Hospital, Sheffield, UK
Spencer J. Collis , email:
Keywords: Glioma, Glioblastoma, Fanconi Anaemia, Temozolomide, Chemo-sensitisation
Received: July 8, 2014 Accepted: July 14, 2014 Published: July 16, 2014
Brain tumours kill more children and adults under 40 than any other cancer. Around half of primary brain tumours are glioblastoma multiforme (GBMs) where treatment remains a significant challenge. GBM survival rates have improved little over the last 40 years, thus highlighting an unmet need for the identification/development of novel therapeutic targets and agents to improve GBM treatment. Using archived and fresh glioma tissue, we show that in contrast to normal brain or benign schwannomas GBMs exhibit re-expression of FANCD2, a key protein of the Fanconi Anaemia (FA) DNA repair pathway, and possess an active FA pathway. Importantly, FANCD2 expression levels are strongly associated with tumour grade, revealing a potential exploitable therapeutic window to allow inhibition of the FA pathway in tumour cells, whilst sparing normal brain tissue. Using several small molecule inhibitors of the FA pathway in combination with isogenic FA-proficient/deficient glioma cell lines as well as primary GBM cultures, we demonstrate that inhibition of the FA pathway sensitises gliomas to the chemotherapeutic agents Temozolomide and Carmustine. Our findings therefore provide a strong rationale for the development of novel and potent inhibitors of the FA pathway to improve the treatment of GBMs, which may ultimately impact on patient outcome.
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