Newcastle University

Background

Research associate at Newcastle University since October 1988, PhD awarded in December 2000 and a senior research associate since January 2002

Roles and Responsibilities

Research Associate Representative and Chair person (2002-2007)
Safety committee member, deputy ACGM officer (1999-2000), (2004-2009)

Qualifications

PhD, Newcastle University (2000)
Fellowship of the Institute of Medical Laboratory Scientific Officers, Newcastle Polytechnic (1988)
BSc (Hons) Botany and Zoology, Leeds University (1983)

Previous Positions

Research Associate 2, Newcastle University (Jan 2002 - present)
Research Associate 1A, Newcastle University (Sept 1997 - Dec 2001)
Junior Research Associate 1B, Newcastle University (Oct 1991 - Aug 1997)

Memberships

Active Member of the American Association for Cancer Research
Member of European Association for Cancer Research

UK Purine Club 

Honours and Awards

AACR-AFLAC Young Investigator Award at the AACR 1999 Special Conference, Molecular Determinants of Sensitivity to Antitumour Agents, Whistler, Canada, February 1999
Young Investigator Award at the European Organisation for Research and Treatment of Cancer, Nancy, France, January 21-24th 1998

Informal Interests

Keeping fit

Research Interests

6-Mercaptopurine, 6-thioguanine and azathioprine metabolism in leukaemia and immunosuppression

Other Expertise

The laboratoy techniques involved in this project broadly encompass, cell culture, (including drug sensitivity, transfection and transduction of specific genes); molecular biological techniques (DNA/RNA isolation, cloning, PCR, Real-time PCR, DNA sequencing, mutation screening); HPLC (enzyme activity analysis, incorporated thioguanine nucleotides into DNA, thiopurine metabolite levels); LC-MS/MS for thiopurine metabolite levels and protein expression analysis (western blotting). computational techniques involve the use of COPASI and CellDesigner.

Current Work

My research focusses on the thiopurine drugs; 6-mercaptopurine (6-MP), 6-thioguanine (6-TG) and the pro-drug of 6-MP, azathioprine. All these drugs have been in clinical use since the 1950's for cancer treatment, as immunosuppressants for the treatment of conditions such as inflammatory bowel disease (IBD) and post organ transplant.

 Thiopurine drugs undergo extensive metabolism, very similar to the normal purine synthesis pathway, in cells before they are able to exert their effects. Thiopurines have been shown by us and others that they mediate their effects by many mechanisms including inhibition of De Novo purine synthesis (DNPS), alterations in DNA methylation, incorporation of thioguanine (dGs) into DNA and disturbances in G-protein signalling. The most extensively-investigated enzyme in the activation of thiopurines is thiopurine methyl-transferase (TPMT), genetic variation of which has consequences for treatment response. Those patients that have no TPMT activity (1/300) have to be treated with about 1/10^th of the normal dose to avoid severe adverse reactions. Some of the other enzymes that mediate thiopurine response include inosine-monophosphate dehydrogenase, inosine tri-phosphatase and methylthioadenosine phosphorylase (MTAP). We published data in showing that expression of MTAP affects thiopurine toxicity substantially in vitro. This is of particular interest in cancer as this gene is situated adjacent to the cell cycle genes p15INK4B, p16INK4A and p14ARF, on chromosome 9p; a locus often deleted in cancer, raising the question of the impact of MTAP deletion in cancer progression or response to drugs that interfere with purine synthesis. This is an area still being investigated using in vitro models. We are also combining thiopurines with other cancer drugs to determine if the thiopurines could be used to enhance efficacy of drugs currently in clinical use and newly developed drugs.

In addition to the focus on cancer I am also interested in the wider use of these drugs particularly as immunosuppressants in the context of IBD (Ulcerative colitis and Crohn’s disease). IBD is an incurable chronic illness affecting about 10-20 individuals per 100,000 in the UK. Relapsing, severe IBD is associated with a shorter, poorer quality of life with a high risk of major abdominal surgery. For IBD patients, azathioprine is the drug of choice as it is safe, effective, and can be used long term, unlike Infliximab, an expensive infused drug. Successful treatment with azathioprine in children allows previously malnourished and growth-stunted children “to catch up” without impacting on fertility, in contrast to methotrexate, the second-choice drug if azathioprine fails. In ~9-26% of IBD patients, adverse drug reactions that require treatment such as infection (7%), pancreatitis (3.3%) and drug-induced hepatitis (0.3%) occur in response to azathioprine or 6-MP. It is therefore clear that a more in depth understanding of the mechanisms of the adverse drug reactions in response to the thiopurines will allow facilitate a more personalised approach to their use.

To help further address this I have two other projects currently running. In collaboration with Drs Redfern (NICR) and Birch-Machin (ICM) we have a project to investigate the contribution of mitochondrial DNA copy number in maintaining purine pools when cells are under stress due to purine inhibition by drugs. The other project is a computational modelling project with Drs Redfern (NICR) and Shanley (IAH). We jointly supervise a PhD student who is developing a mathematical model of purine and thiopurine metabolism using a systems biology approach, to identify new mechanisms of action with a long term aim of using this type of approach in the clinical context.

The main themes to be taken forward to allow individualised treatment with thiopurines include thioguanine nucleotide incorporation in nuclear and mitochondrial DNA; the role of thio-GTP in GTP-cell signalling pathways; induction of apoptotic and autophagic responses, and the impact of disturbances in purine levels in cancer and IBD. This will include both a laboratory and a computational biology approach.

Future Research

The ultimate goal of this research is to broaden the understanding of thiopurine toxicity based on genetic background of the cell type. Future research will concentrate on correlating the in vitro evidence to the clinical setting so that individualisation of patient treatment can be achieved.

Postgraduate Supervision

Supervision of PhD students: Sotiris Georgantopoulos (2004-7); Nadia Thornton (2002-5); Mark Leslie (2000-3); Dr. Margaret Little (joint supervisor 1998-200)

Esteem Indicators

Travel Fellowships:
Visiting Fellow to Linköping University, Sweden September 2009-June 2010
EACR Travelling Fellowship to Linköping University, Sweden, February 2010
Visiting Fellow to Linköping University, Sweden, September 2007-November 2009.

Invited Oral presentations:
1. Purines, Tarragona, Spain, 2010
2. Purine and Pyrimidines in Man, Stockholm, 2009
3. The Epigenetic Effects of the Thiopurines, Glaxo-Smith-Kline, Harlow, UK.15 June 2005.
4. Purine and Pyrimidines in Man, Egmond aan Zee, Netherlands (2003).
Visits for collaborative discussions with:
1. Dr B Brown, Department of Medical Oncology, Cancer Research UK (2002
2. Dr Howard McLeod, Washington University School of Medicine Department of Medicine, St Louis, MO, USA (2002).
Awards:
1. AACR-AFLAC Young Investigator Award at the AACR 1999 Special Conference, Molecular Determinants of Sensitivity to Antitumour Agents, Whistler, Canada, February 1999.
2. Young Investigator Award at the European Organisation for Research and Treatment of Cancer, Nancy, France, January 21-24th 1998
Book chapters:
1. Jamieson D, Coulthard SA, Boddy AV in Handbook of anticancer pharmacokinetics and pharmacodynamics (2nd Edition), W.D. Figg and H.L. McLeod, Editors. Human Press: Totowa, New Jersey. In Press
2. Coulthard SA and Boddy AV "Metabolism (Non-CYP enzymes)" in "Pharmacokinetics and Pharmacodynamics of Anti-Cancer Drugs" (eds Figg WD and McLeod HM), Humana Press Inc New Jersey USA (2004).
3. Hall A., Hogarth L., Matheson E., Foster S. Characterisation of the Role of Cytosolic “Glutathione S-Transferase in the conjugation of Glutathione to Melphalan in drug resistance in Leukemia and Lymphoma”. The Clinical Value of Laboratory Studies edited by Kaspers, G.J.L., Pieters, R., Twentyman, P.R., Weisenthal, L.M., Veerman, A.J.P Harwood Academic Publishers Switzerland. (1993)

Funding

1. C.P.F. Redfern; Daryl P. Shanley; Sally A. Coulthard: Computational modelling of the interactions between pathways of DNA damage and nucleotide synthesis. BBSRC DTG PhD studentships in the area “Systems approach to biological research” (£70,000)
2. CPF Redfern, Sally Coulthard (co-principal investigator), Ruth Plummer and Hilary Calvert Expanding the therapeutic range of thiopurine drugs. Cancer Research UK (£70,339)
3. Andy Hall, Sally Coulthard, Linda Hogarth, Julie Irving and Liz Matheson Childhood leukaemia molecular pharmacology programme(£595,536) Leukaemia Research Fund
4. N.J. Curtin E.R. Plummer S.A. Coulthard Poly (ADP-ribose) polymerase pharmacogenetics and pharmacoproteomics in patients receiving anticancer therapy (£75,010) AICR
5. S.Coulthard, M.Leslie and A.G.Hall Transcriptional regulation of asparagine synthetase expression (£75,540) Tyneside Leukaemia Research Fund, 1st October 2004-30th September 2007.
6. Hogarth,L.A., Coulthard,S.A., Hall,A.G. The Role of p21 CIP/WAF/SD11 inactivation in acute lymphoblastic leukaemia (£45,231) Tyneside Leukaemia Research Fund, 1st October 2003-30th September 2006.
7. Coulthard, S.A., Hall,A.G. Lometrexol-Selective treatment for relapsed childhood Leukaemia? (£53,670) Tyneside Leukaemia Research Fund, 1st October 2002-30th September 2005.
8. Hall, A.G., Coulthard, S.A., Hogarth, L.A., Irving, J.A.E. Optimisation of Chemotherapy in Childhood Acute Lymphoblastic Leukaemia. (£1,391,876): Leukaemia Research Fund, 1st April 2002- 31st March 2007.
9. Kearns,P.R., Boddy, A., Coulthard, S., Curtin, N.J., Hall, A.G., Newell, D.R., Pearson, A.D.J., Application for a Clinician Scientist with responsibility for early clinical studies of new anti-leukaemic agents in children. (£257,388): Leukaemia Research Fund 2001-2004.
10. Hall, A.G., Hogarth, L.A., Coulthard, S.A., Pearson, A.D.J., The Role of Thiopurine Methyltransferase in determining Sensitivity to Thiopurine Drugs (£49,724): Leukaemia Research Fund (Clinical Training Fellowship) 1st June 2001 – 31st May 2002.
11. Hall, A.G., Case, M.C. and Coulthard, S.A. A Study of the cytotoxic effect of Buthionine Sulphoxide in neuroblastoma (£70,869): North of England Children’s Cancer Research Fund.1st July 1998 –30th June 2000.

Keywords

Thiopurine
6-Mercaptopurine
6-thioguanine
azathioprine

Leukaemia

Inflammatory bowel disease 

Undergraduate Teaching

 give lectures and seminars to BSc students on the Advanced Pharmacogenetics module (PED3005) and supervise students on the undergraduate BSc projects module CMB3000.

Postgraduate Teaching

I give lectures and seminars on the Medical and Molecular Biosciences MRes Systems Biology module (MMB8023). 

I have supervised 7 PhD students as detailed below:

1.   Sarah McGarrity (PhD student), co-supervisor “Computation modelling of the interactions between pathways of DNA damage and nucleotide synthesis” BBSRC, 1^st October 2010-30^th September 2013

2.   Tomasz Zaremba (PhD student), co-supervisor “Poly (ADP-ribose) polymerase pharmacogenetics and pharmacoproteomics in patients receiving anticancer therapy” AICR 1^st October 2006- 30^th September 2009

3.   Sotiris Georgantopoulos (PhD student), principal supervisor: “Transcriptional regulation of asparagine synthetase expression”. Tyneside Leukaemia Research Fund, 1^st October 2004-30^th September 2007

4.   Nadia Thornton (PhD student), principle supervisor: “Lometrexol-Selective treatment for relapsed childhood leukaemia?” Tyneside Leukaemia Research Fund October 2002- September 2005.

5.   Mark Leslie, (PhD student) principle supervisor: “The Molecular Basis of Resistance to L-asparaginase in vivo” Leukaemia Research Fund, Gordon Pillar Studentship October 2000-September 2003.

6.   Lisa Bloodworth, (PhD student) co-supervisor: “Mechanisms of drug resistance in mismatch repair deficient cells” Tyneside Leukaemia Research Fund October 2000-September 2003.

7.   Dr Margaret Little, (Clinical Training Fellowship; PhD) co-supervisor: “The Role of Thiopurine Methyltransferase in determining Sensitivity to Thiopurine Drugs” October 1998-May 2002. Funded by the Leukaemia Research Fund.

• Coulthard SA, Redfern CPF, Vikingsson S, Lindqvist-Appell M, Skoglund K, Jakobsen-Falk I, Hall AG, Taylor GA, Hogarth LA. Increased Sensitivity to Thiopurines in Methylthioadenosine Phosphorylase-Deleted Cancers. Molecular Cancer Therapeutics 2011, 10(3), 495-504.
• Zaremba T, Thomas HD, Cole M, Coulthard SA, Plummer ER, Curtin NJ. Poly(ADP-ribose) polymerase-1 (PARP-1) pharmacogenetics, activity and expression analysis in cancer patients and healthy volunteers. Biochemical Journal 2011, 436(3), 671–679.
• Fotoohi AK, Coulthard SA, Albertioni F. Thiopurines: Factors influencing toxicity and response. Biochemical Pharmacology 2010, 79(9), 1211-1220.
• Plummer ER, Vidal L, Griffin MJ, Lesley M, de Bono J, Coulthard SA, Sludden J, Siu LL, Chen EX, Oza AM, Reid GK, McLeod AR, Besterman JM, Lee C, Judson I, Calvert AH, Boddy AV. Phase I Study of MG98, an Oligonucleotide Antisense Inhibitor of Human DNA Methyltransferase 1, Given as a 7-Day Infusion in Patients with Advanced Solid Tumors. Clinical Cancer Research 2009, 15(9), 3177-3183.
• Zaremba T, Ketzer P, Cole M, Coulthard S, Plummer ER, Curtin NJ. Poly(ADP-ribose) polymerase-1 polymorphisms, expression and activity in selected human tumour cell lines. British Journal of Cancer 2009, 101(2), 256-262.
• Stanulla M, Schaeffeler E, Möricke A, Coulthard SA, Cario G, Schrauder A, Kaatsch P, Dördelmann M, Welte K, Zimmermann M, Reiter A, Eichelbaum M, Riehm H, Schrappe M, Schwab M. Thiopurine methyltransferase genetics is not a major risk factor for secondary malignant neoplasms after treatment of childhood acute lymphoblastic leukemia on Berlin-Frankfurt-Munster protocols. Blood 2009, 114(7), 1314-1318.
• Hogarth LA, Redfern CPF, Teodoridis J, Hall AG, Anderson HL, Case MC, Coulthard SA. The effect of thiopurine drugs on DNA methylation in relation to TPMT expression. Biochemical Pharmacology 2008, 76(8), 1024-1035.
• Leslie M, Case MC, Hall AG, Coulthard SA. Expression levels of asparagine synthetase in blasts from children and adults with acute lymphoblastic leukaemia. British Journal of Haematology 2006, 132(6), 740-742.
• Coulthard, S.A., Hogarth, L.A., Little, M.A., Matheson, E., Redfern, C.P.F., Minto, C.L.J., Hall, A.G. The effect of thiopurine methyltransferase expression on sensitivity to thiopurine drugs. Molecular Pharmacology 2002, 62(1), 102-109.
• Coulthard SA, Howell CI, Robson J, Hall AG. The relationship between thiopurine methyltransferase activity and genotype in blasts from patients with acute leukemia. Blood 1998, 92(8), 2856-2862.