Newcastle University

Introduction

My principal research interest is in the molecular pathogenesis of gastrointestinal tumours. In particular this involves the characterisation of the novel tumour suppressor gene KLF6 in these cancers, as well as the application of gene profiling in the detection, prognostication and classification of these diseases. During the corse of these studies, my group has identified novel pathways predisposing to the development and progression of chronic liver disease to cirrhosis and cancer, as well as candidates for therapeutic developent as drug targets.  My appointment is within the Northern Institute for Cancer Research, within which I collaborate closely with memebers of the Clinical and Translational and Drug Development groups. However, I maintain strong clinical and research links with the Liver Group and have initiated the Gastroenterology Reserach Tissue bank, which is central to our translational research projects.

Roles and Responsibilities

My clinical role is that of lead physician within the Hepatopancreatobiliary (HPB) Newcastle Hospitals NHS Foundation Trust, co-ordinating the care of patients with hepatocellular cancer in the North East. Referrals to this service have increased 10 fold in the last decade.

My research role and responsibility is that of a senior lecturer and lead PI in the Gastroenterology group in the Northern Institute for cancer research.  Presently my group includes 1 post doctoral scientist, 3 PhD students, 2 MD students and one clinical research associate. 

Qualifications

BMedSci, BM, BS, FRCP, PhD

Previous Positions

Nottingham City Hospital, JHO. Prof. AE Tattersfield 1990-91
Derby City Hospital, House Surgeon. Mr KG Callum. 1991
Newcastle Teaching Hospitals Medical SHO Rotation 1991-93
Clinical Research Associate University of Newcastle upon Tyne1993-97
Honorary Clinical Registrar, Freeman Hospital 1993-97
SpR in General Medicine and Gastroenterology 1997-00 Royal Victoria Infirmary (Newcastle-upon-Tyne) 1997-98 North Tees General Hospital (Stockton-on-Tees) 1998-99 South Cleveland Hospital (Middlesborough) 1999-00
Postdoc, Mount Sinai School of Medicine, New York, USA 2000-03
SpR Freeman Hospital (FH) 2003-03
GlaxoSmithKline Senior Lecturer 2003

Memberships

Member of the Royal College of Physicians
European Association for Study of the Liver
British Association for Study of the Liver

International Liver Cancer Association  

Honours and Awards

British Liver Trust laboratory support grant 1994
Wellcome Trust Clinical Training Fellowship 1995 Dewar Research Prize, Northern Association of Physicians 1997
Peel Medical Research Trust Travel Award 2000
American Association for Study of Liver Diseases Fellowship 2001 GlaxoSmithKline Senior Fellowship 2002
European Brewers Association Research Award 2003 Special Trustees Award 2003

GlaxoSmithKline Senior Clinician Scientist award 2003-2008 

Languages

English

Research Interests

• Molecular pathogenesis of gastrointestinal cancers
• The Role of the tumour suppressor gene Kruppel-like Factor 6 (KLF6) in the development and progression of chronic liver disease to cirrhosis and hepatocellular cancer (HCC)
• The role of KLF6 in hepatic glucose regulation and the development of non alcoholic fatty liver disease (NAFLD)
• KLF6 as a predictive biomarker in colorectal cancer progression
• KLF6 in chemotherapy induced liver injury (KLF6) 
• Type 2 diabetes, obesity and HCC
• Exploitation of the DNA damage response (DDR) as a targeted therapy for patients with HCC 
• The role of Sulfatase-2 (SULF2) in NAFLD progression and HCC
• SULF-2 as a drug development target in HCC and pancreatic cancers 

 Other Expertise

• Microarray analyses
• The application of serum proteomics to chronic liver disease and HCC
• Animal models of NAFLD and HCC 

Current Work

• Characterisation of KLF6 in premalignant and malignant gastrointestinal disease
• Characterisation of the KLF6IVS1-27G>A polymorphism in NAFLD and HCC
• Exploration of KLF6 in the regulation of glucokinase and hepatic glucose metabolism
• Exploration of KLF6 in chemotherapy induced liver injury (CALI)
• Identification and characterisation of serum biomarkers for the surveillance of HCC
• Inhibition of DNA Repair as a treatment strategy for HCC
• SULF2 as a therapeutic candidate for patients with HCC and pancreatic cancers

Future Research

• Development of biomarkers for HCC surveillance and guiding targeted therapy for those affected

• Development of therapeutoc stratagies to prevent HCC development

• Development of targeted therapies for patients with HCC 

Research Roles

• Group leader
• Supervisor of MD and PhD students
• Supervisor of undegraduate students
• PI for HPB and gastroenterology reserach tissue bank 

Postgraduate Supervision

1. One post doctoral researcher
2. One clinical research associate

Esteem Indicators

• Publications.
• Awarded grants
• Invited lectures and session chair at National and International meetings

Funding

• FP7 funded project 'FLIP' - Fatty Liver Inhibition of Progression. Subproject - The Role of KLF6 in the development and progression of HCC'.
• LiverNorth studentship - DNA-PK as a therapeutic strategy in HCC
• CR UK Bursary to Kei Hui - KLF6 in CALI
• Peel medical research trust - KLF6 as a predictive biomarker in colorectal cancer

Industrial Relevance

Hoping to engage industrial partners in serum biomarker projectsnone

Keywords

• Hepatocellular cancer
• HCC
• KLF6
• Alternative splicing
• proteomincs
• DNA-PK
• DDR
• SULF2
• CALI
  

Undergraduate Teaching

• Informal clinical ward based teaching on a monthly basis
• Lecturer on CSIM3 course
• Undergraduate tutor
• Undergraduate students - 2 honours projects students and 2 Mres students

Postgraduate Teaching

• Lecturer to Gastroenterology SpRs
• Lecturer to Oncology SpRs
• Lecturer to Transplant co-ordinators
• Informal ward based clinical teaching
• Non- clinical - PhD students; MD students

• Patman GL, Anstee Q, Reeves HL. Hepatocellular Carcinoma in NASH: Is there a biological Rationale?. In: 9th Meeting of Therapy in Liver Diseases. 2011, Barcelona, Spain.
• Lochan R, Daly AK, Reeves HL, Charnley R. The role of tobacco derived carcinogens in pancreas cancer. ISRN Oncology 2011, 249235.
• Bechmann LP, Vetter D, Hannivoort RA, Patman G, Lee UE, Fiel MI, Agius L, Reeves H, Friedman SL. Liver-specific deletion of KLF6 uncovers novel transcriptional pathways linked to lipid and glucose homeostasis. In: 61st Annual Meeting of the American Association for the Study of Liver Diseases. 2010, Boston, MA: Hepatology: Wiley-Blackwell.
• Cornell L, Munck JM, Budhisetiawan F, Newell DR, Bardos JI, Manas D, Curtin NJ, Reeves H. Synthetic lethality in liver cancer cell lines treated with inhibitors of DNA double strand break repair. In: 61st Annual Meeting of the American Association for the Study of Liver Diseases. 2010, Boston, MA: Hepatology: Wiley-Blackwell.
• Miele L, Beale G, Patman G, Nobili V, Leathart J, Grieco A, Abate M, Friedman S, Narla G, Bugianesi E, Day C, Reeves H. The Kruppel-like factor 6 genotype is associated with fibrosis in nonalcoholic fatty liver disease. Gastroenterology 2008, 135(1), 282-291.e1.
• Gray J, Chattopadhyay D, Beale GS, Patman GL, Miele L, King BP, Stewart S, Hudson M, Day CP, Manas DM, Reeves HL. A proteomic strategy to identify novel serum biomarkers for liver cirrhosis and hepatocellular cancer in individuals with fatty liver disease. BMC Cancer 2009, 9.
• Beale GS, Chattopadhyay D, Gray J, Stewart SF, Hudson M, Day CP, Trerotoli P, Giannelli G, Manas DM, Reeves HL. AFP, PIVKAII, GP3, SCCA-1 and follisatin as surveillance biomarkers for hepatocellular cancer in non-alcoholic and alcoholic fatty liver disease. BMC Cancer 2008, 8, 200.
• Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J. Sorafenib in advanced hepatocellular cancer. N Engl J Med 2008, 359, 378-90.
• Lochan R, Daly AK, Reeves HL, Charnley RM. Genetic susceptibility in pancreatic ductal adenocarcinoma. British Journal of Surgery 2008, 95(1), 22-32.
• Bechmann LP, Gastaldelli A, Vetter D, Patman GL, Pascoe L, Hannivoort RA, Lee UE, Fiel I, Muñoz U, Ciociaro D, Buzzigoli E, Miele L, Hui KY, Bugianesi E, Burt AD, Day CP, Mari A, Agius L, Walker M, Friedman SL, Reeves HL. Glucokinase links Krüppel-like factor 6 to the regulation of hepatic insulin sensitivity and non alcoholic fatty liver disease. Hepatology 2012, 55(4), 1083-1093.
• Das D, Chattopadyhay D, Patanwala I, Islam T, Walia D, Rose J, Jaques B, Manas DM, Hudson M, Reeves HL. NAFLD and the changing face of hepatocellular cancerER (HCC). In: Journal of Hepatology: 46th Annual Meeting of the European Association for the Study of the Liver (EASL). 2011, Berlin, Germany: Elsevier BV.
• Graham JE, Aslam T, Chattopadyhay D, Das D, Patanwala I, Rose J, Jaques BC, Manas D, Hudson M, Reeves H. NAFLD related HCC is rising dramatically in the North of England. In: Hepatology: 62nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). 2011, San Francisco, California, USA: John Wiley & Sons, Inc.
• Cornell L, Munck J, Alsinet C, Villanueva A, Thomas H, Jackson J, Televantou D, Burt A, Llovet JM, Curtin N, Reeves HL. DNA-PK in hepatocellular cancer - a driver of progression and chemoradioresistance?. Will try Nature Medicine or Gastroenterology 2013. In Preparation.
• Reeves HL, Chattopadyhay D, Lochan R, Graham J, Das D, Aslam T, Patanwala I, Gaggar S, Cole M, Jaques B, Sumpter K, Stewart S, Rose J, Hudson M, Manas D. Hepatocellular Cancer – the impact of obesity and type 2 diabetes. Journal of Hepatology 2013. Submitted.
• Patman GL, Televantou D, Whitehead A, Oakley F, Mann DA, Burt AD, Anstee QA, Reeves HL. NAFLD progression to NASH, fibrosis and hepatocellular cancer - development of a robust animal model. Journal of Hepatology 2013. In Preparation.
• Bechmann LP, Vetter D, Ishida J, Hannivoort RA, Lang UE, Kocabayoglu P, Fiel MI, Muñoz U, Patman GL, Ge F, Yakar S, Li X, Agius L, Lee YM, Zhang W, Hui KY, Televantou D, Schwartz GJ, Leroith D, Berk PD, Nagai R, Suzuki T, Reeves HL, Friedman SL. Post-transcriptional activation of PPAR alpha by KLF6 in hepatic steatosis. Journal of Hepatology 2013, 58(5), 1000-1006.
• Alhasan S, Patman GL, Televantou D, Beale G, Wedge S, Newell DR, Reeves HL. Sulfatase-2 (SULF2) expression in hepatocellular cancer cells or tumour activated stromal cells associates with membranous translocation of beta catenin and a poor prognosis. Cancer Research 2013. In Preparation.
• Cornell L, Munck J, Curtin N, Reeves H. DNA-PK or ATM inhibition inhibits non-homologous end joining and enhances chemo- and radio sensitivity in hepatocellular cancer cell lines. In: Digestive Disorders Federation Meeting. 2012, Liverpool, UK: BMJ Group.
• Anstee QM, Darlay R, Leathart JB, Clement J, Clement K, Aithal GP, Valenti L, Van Gaal L, Stickel F, Allison ME, Romero-Gomez M, Andrade RJ, Reeves H, Pihlajamaki J, Bedossa P, Kotronen A, Yki-Jarvinen H, Chalasani NP, Kleiner DE, Rotter J, Burt AD, Ratziu V, Cordell HJ, Daly AK, Day CP. Genome-Wide Association Analysis Confirms Importance of PNPLA3 and Identifies Novel Variants Associated With Histologically Progressive Steatohepatitis in NAFLD. In: 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD). 2012, Boston, Massachusetts, USA: John Wiley & Sons, Inc.
• Hui KYD, Robinson S, Patman GL, Manas D, Reeves HL, White S. KLF6 splice variant 1 in patients with colorectal liver metastasis correlates with a higher clinical risk score. In: Digestive Disorders Federation Meeting. 2012, Liverpool, UK: BMJ Group.
• Patman GL, Hui KY, Anstee QM, Reeves HL. Kruppel-like factor 6 splice variant 3 (KLF6-SV3) - The redox sensitive splice variant of KLF6 expressed in non-alcoholic steatohepatitis (NASH). In: 47th Annual Meeting of the European Association for the Study of the Liver (EASL). 2012, Barcelona, Spain: Elsevier BV.
• Televantou D, Hui KYD, Lochan R, Charnley R, Burt AD, Reeves HL. Membranous expression of sulfatase-2 is associated with a poorer prognosis in patients following pancreatic cancer resection. In: Digestive Disorders Federation Meeting. 2012, Liverpool, UK: BMJ Group.
• Patman G, Hui KY, Anstee QM, Reeves HL. Oxidative stress induces alternative splicing and nuclear translocation of kruppel like factor 6. In: Digestive Disorders Federation Meeting. 2012, Liverpool, UK: BMJ Group.
• Alhasan SF, Beale GS, Newell DR, Reeves HL. Suppression of SULF2, an extracellular endosulfatase up-regulated in hepatocellular cancers, modulates WNT signalling and inhibits cell growth. In: Digestive Disorders Federation Meeting. 2012, Liverpool, UK: BMJ Group.