title: FANCD2 re-expression is associated with glioma grade and chemical inhibition of the Fanconi Anaemia pathway sensitises gliomas to chemotherapeutic agents.
abstract: 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, where 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.
authors: Sheffield Cancer Research Centre, Academic Unit of Molecular Oncology, Department of Oncology, University of Sheffield Medical School, Beech Hill Road, Sheffield, UK.
authors: Abhijit A
authors: AA
authors: Patil
authors: Neuro-Oncology Group, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield, UK.
authors: Parag
authors: P
authors: Sayal
authors: Sheffield Cancer Research Centre, Academic Unit of Molecular Oncology, Department of Oncology, University of Sheffield Medical School, Beech Hill Road, Sheffield, UK.
authors: Marie-Lise
authors: ML
authors: Depondt
authors: Sheffield Cancer Research Centre, Academic Unit of Molecular Oncology, Department of Oncology, University of Sheffield Medical School, Beech Hill Road, Sheffield, UK.
authors: Ryan D
authors: RD
authors: Beveridge
authors: Neuro-Oncology Group, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield, UK.
authors: Anthony
authors: A
authors: Roylance
authors: Sheffield Cancer Research Centre, Academic Unit of Molecular Oncology, Department of Oncology, University of Sheffield Medical School, Beech Hill Road, Sheffield, UK.
authors: Deepti H
authors: DH
authors: Kriplani
authors: Sheffield Cancer Research Centre, Academic Unit of Molecular Oncology, Department of Oncology, University of Sheffield Medical School, Beech Hill Road, Sheffield, UK.
authors: Katie N
authors: KN
authors: Myers
authors: Sheffield Cancer Research Centre, Academic Unit of Molecular Oncology, Department of Oncology, University of Sheffield Medical School, Beech Hill Road, Sheffield, UK.
authors: Angela
authors: A
authors: Cox
authors: Neuro-Oncology Group, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield, UK.
authors: David
authors: D
authors: Jellinek
authors: Department of Histopathology, Sheffield Teaching Hospitals, Royal Hallamshire Hospital, Sheffield, UK.
authors: Malee
authors: M
authors: Fernando
authors: Neuro-Oncology Group, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield, UK.
authors: Thomas A
authors: TA
authors: Carroll
authors: Sheffield Cancer Research Centre, Academic Unit of Molecular Oncology, Department of Oncology, University of Sheffield Medical School, Beech Hill Road, Sheffield, UK.
authors: Spencer J
authors: SJ
authors: Collis
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002330:Carmustine / Q000494:pharmacology; D045744:Cell Line, Tumor; D003474:Curcumin / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000096:biosynthesis*; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D060787:Neoplasm Grading; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D003606:Dacarbazine; D003474:Curcumin; D002330:Carmustine; D000077204:Temozolomide