Brain Tumour Research at the University of Wolverhampton

The University of Wolverhampton is a founder member of Brain Tumour North West (BTNW), www.braintumournw.org/index.html.

This is a strategic alliance broadly based within the north west of England and where all members are within about 90 minutes travel time of each other. The aim of the alliance is to share scarce resources available for neuro-oncology, develop multidisciplinary collaborations and deploy these resources to answer important questions (laboratory-based or clinical) in neuro-oncology in a timely fashion. We envisage that such cooperation would provide the infrastructure to translate laboratory findings into clinical practice rapidly and effectively. At present, BTNW comprises the University of Central Lancashire, University of Wolverhampton and Lancashire Teaching Hospitals NHS Foundation Trust, Manchester Metropolitan University, Keele University, Liverpool University and their associated NHS Trusts.

Professor John Darling’s research at the University of Wolverhampton is based in the Research Institute in Healthcare Science (www.wlv.ac.uk/rihs). He is presently working in three main areas of brain tumour research.

The first is centred on the molecular genetic changes that occur during the development of brain tumours. This work has been carried out in collaboration with Dr Tracy Warr’s research group at the Institute of Neurology, National Hospital for Neurology and Neurosurgery, University College, London.

Potter N Karakoula A Phipps KP Harkness W Hayward R Thompson DN Jacques TS Harding B Thomas DGT Palmer RW Rees J Darling J Warr TJ Genomic deletions correlate with underexpression of novel candidate genes at six loci in pediatric pilocytic astrocytoma. Neoplasia 10: 757-72 2008
Suarez-Merino B Hubank M Revesz T Harkness W Hayward R Thompson D Darling JL Thomas DGT Warr TJ Microarray analysis of pediatric ependymoma identifies a cluster of 112 candidate genes including four transcripts at 22q121-q133 Neuro-oncology 2005 7: 20 – 31
Ward S Harding B Wilkins P Harkness W Hayward R Darling JL Thomas DG Warr T Gain of 1q and loss of 22 are the most common changes detected by comparative genomic hybridisation in paediatric ependymoma Genes Chromosomes Cancer 32: 59-66 2001
Warr TJ Ward SJ Burrows J Harding B Wilkins P Harkness W Hayward R Kitchen N Darling JL and Thomas DGT Identification of extensive genomic loss and gain by comparative genomic hybridisation in malignant astrocytoma in children and young adults Genes Chromosomes and Cancer 31: 15-22 2001

His second major area of research has been around why so many types of brain tumour are resistant to chemotherapy and developing new types of therapy. He has been working with colleagues at the University of Wolverhampton developing new tumour homing peptide molecules (with Professor John Howl and Dr Ian Nichol and supported by the Samantha Dickson Brain Tumour Trust) and trying to identify which intracellular molecules in brain tumours produce drug resistance and how these might be used to make new drugs for brain tumour chemotherapy (with Dr Weiguang Wang and Dr Sarah Brown and again supported by the Samantha Dickson Brain Tumour Trust). A particular emphasis has been on using gene therapy to increase the sensitivity of brain tumour cells to chemotherapy. Three PhD students, Donna Brown, Liz Goessl and Vicky Wootton, are presently undertaking research on drug resistance in brain tumours.

Guo X Evans TRJ Somanath S Armesilla AL Darling JL Schatzlein A Cassidy J Wang W In vitro evaluation of cancer-specific NF-kB-CEA enhancer-promoter system for 5-fluorouracil prodrug gene therapy in colon cancer cell lines Br J Cancer 97: 483-492 2007
Mall JK Darling J Patel B Howl J Cell penetrating nanoparticles for fluorescent imaging and therapeutic applications J Peptide Sci 12: 236 2006
Darling JL Molecular pathology of brain tumours - How will molecular and cell biology contribute to improved outcomes in patients with malignant brain tumours? Biomed Papers Medical Faculty Palacky University Olomouc Czech Republic 150: Suppl 1 20-22 2006
Darling JL Drug resistance in malignant brain tumours In: The molecular and cellular pathology of cancer progression and prognosis ed GV Sherbet Research Signpost Trivandrum 409-430 2006
Darling JL Cellular mechanisms behind therapeutic resistance MIMS Advances in Neuro-oncology Issue 2: 2-5 2005
Petch AK Sohail M Hughes MD Benter I Darling J Southern EM Akhtar S Messenger RNA expression profiling of genes involved in epidermal growth factor receptor signalling in human cancer cells treated with scanning array-designed antisense oligonucleotides Biochem Pharmacol 66: 819-30 2003
Cowen RL Williams JC Emery S Blakey D Darling JL Lowenstein PR Castro MG Adenovirus vector-mediated delivery of the prodrug-converting enzyme carboxypeptidase G2 in a secreted or GPI-anchored form: High-level expression of this active conditional cytotoxic enzyme at the plasma membrane Cancer Gene Ther 9: 897-907 2002
Darling JL Thomas DG Response of short-term cultures derived from human malignant glioma to aziridinylbenzoquinone etoposide and doxorubicin: an in vitro phase II trial Anticancer Drugs 12: 753-60 2001
Maleniak TC Darling JL Lowenstein PR Castro MG Adenovirus-mediated expression of HSV1-TK or Fas ligand induces cell death in primary human glioma-derived cell cultures that are resistant to the chemotherapeutic agent CCNU Cancer Gene Ther 8: 589-98 2001

A developing area of research has been around identifying and characterising so celled “brain tumour stem cells” that are now thought to be the important cells to kill with chemotherapy. Work undertaken in collaboration with Dr Sarah Brown and more recently Dr Bahareh Vahabi and supported by the Bill O’Sullivan Memorial Fund, the Roderick Marsden Charitable Trust and the European Association of Cancer Research in this important emerging area of brain tumour research.

Knizetova P Darling JL Bartek J Vascular endothelial growth factor in astroglioma stem cell biology and response to therapy J Cell Mol Med 12: 111-125 2008
Darling JL In vitro culture of malignant brain tumours In: Culture of tumour cells eds R Pfragner and RI Freshney John Wiley and Sons Ltd New York 349-372 2004