Clinical & Translational Research > Blood Malignancies > Professor Richard Clark

Our research group is active in both clinical and laboratory studies in chronic myeloid leukaemia (CML). The clinical part of the group runs a portfolio of early clinical trials in CML and acute leukaemia, and increasingly in stem cell transplantation. In addition, I chair the CML subgroup of the National Cancer Research Institute and am on the Study Management Committee of both UK SPIRIT trials. Laboratory interests are: Mechanisms of resistance to imatinib Although imatinib is a major step forward in CML treatment, we have shown in a population study that up to 50% of patients may ultimately fail the drug.

We were the first to report that cellular imatinib uptake is an active process, mediated by human Organic Cation Transporter 1 (hOCT1, SLC22A1). We have gone on to show that the level of expression of this transporter is a powerful determinant of the clinical outcome of imatinib treatment, and that the second generation TKIs are taken into cells independently of hOCT1. Current work focuses on the control of hOCT1 expression, and on whether single nucleotide polymorphisms (SNP) in transporters and p450 cytochromes affect clinical responses to TKIs, in a large Kay Kendall Leukaemia Fund-supported study. In a related Leukaemia and Lymphoma Research Fund (LLR) supported study, we are investigating the clinical importance of plasma TKI monitoring. Immune Mechanisms in CML Building on earlier laboratory work, the LRF have supported a phase I/II clinical trial of vaccination of CML patients with BCR-ABL peptides. The phase I component of this trial has shown a high frequency of Tcell response and decrease in the leukaemic burden, with minimal toxicity.

Saglio G, Kim D-W, Issaragrisil S, le Coutre P, Etienne G, Lobo C, Pasquini R, Clark RE, Hochhaus A, Hughes TP, Gallagher N, Hoenekopp A, Dong M, Haque A, Larson RA, Kantarjian HM.  ENESTnd: A randomized comparison of nilotinib and imatinib for newly diagnosed chronic myeloid leukemia.  New England Journal of Medicine 2010; 362: 2251-2259.

Davies A, Jordanides NE, Giannoudis A, Lucas CM, Hatziieremia S, Harris RJ, Jorgenson HG, Holyoake TL, Pirmohamed M, Clark RE, Mountford JC.  Nilotinib concentration in cell lines and  CD34+ chronic myeloid leukaemia cells is not mediated by active uptake or efflux by major drug transporters.  Leukemia 2009, 23: 1999-2006.

Punekar M, Thachil J, Salim R, Watmough S, Clark RE.  T-cell function in chronic myeloid leukemia and its treatment with tyrosine kinase inhibitors - clues from and for sarcoidosis.  Leukaemia Research 2009; 33: e91-92.

Riley CL, Mathieu MG, McArdle SEB, Clark RE, Rees RC.  Immunotherapy for chronic myeloid leukaemia: is it still viable?  Cancer Immunology, Immunotherapy 2009; 58: 1489-1499.

Drummond MW, Heaney N, Kaeda J, Nicolini FE, Clark RE, Wilson G, Shepherd P, Tighe J, McLintock L, Hughes T, Holyoake TL. A pilot study of continuous imatinib mesylate vs. pulsed imatinib with or without rHu-G-CSF in CML patients who have achieved a complete cytogenetic response (GIMI).  Leukemia 2009; 23: 1199-1201.

Rusakiewicz S, Aubert G, Clark RE, Madrigal AJ, Dodi AI, Travers PJ.  Soluble HLA/peptide monomers cross-linked with co-stimulatory antibodies onto a streptavidin core molecule efficiently stimulate antigen-specific T cell responses.  Cancer Immunol Immunother. 2009; 58: 1459-1470.

Clark RE.  Facts and uncertainties in monitoring treatment response in chronic myeloid leukaemia.  Leukaemia Research 2009; 33: 1151-1155. [review].

Grimwade D, Jovanovic JV, Hills RV, Nugent EA, Patel Y, Flora R, Diverio D, Jones K, Aslett H, Batson E, Rennie K, Angell R, Clark RE, Solomon E, Lo-Coco F, Wheatley K, Burnett AK.  Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and direct pre-emptive arsenic trioxide therapy.  Journal of Clinical Oncology 2009; 27: 3650-3658.

Lucas CM, Harris RJ, Giannoudis A, Knight K, Watmough SJ, Wang L, Clark RE.  Chronic myeloid leukaemia patients with the e13a2 BCR-ABL fusion transcript have inferior responses to imatinib than e14a2 patients.  Haematologica 2009, 94: 1362-1367.

Patel B, Kirkland KE, Szydlo R, Pearce RM, Clark RE, Craddock C, Liakopolou E, Fielding AK, Mackinnon S, Olavarria E, Potter MN, Russell NH, Shaw B, Cook G, Goldstone AH, Marks DI.  Favourable outcomes of T-cell depleted unrelated donor stem cell transplantation in adults with high risk Philadelphia chromosome negative acute lymphoblastic leukaemia in first remission.  Haematologica 2009; 94: 1399-1406.

Davies A, Jordanides NE, Giannoudis A, Lucas CM, Hatziieremia S, Harris RJ, Jorgenson HG, Holyoake TL, Pirmohamed M, Clark RE, Mountford JC.  Nilotinib concentration in cell lines and  CD34+ chronic myeloid leukaemia cells is not mediated by active uptake or efflux by major drug transporters.  Leukemia 2009, 23: 1999-2006.

Shaw BE, Mayor NP, Russell NH, Apperley JF, Clark RE, Cornish J, Darbyshire P, Ethell ME, Goldman JM, Little A-M, Mackinnon S, Marks DI, Pagliuca A, Thomson K, Marsh SGE, Madrigal JA.  Diverging effects of HLA-DPB1 matching status on outcome following unrelated donor transplantation is dependent upon disease stage and the degree of matching for other HLA alleles.  Leukemia 2010; 24: 58-65.

Davies A, Hayes A, Pirmohamed M, Clark RE.  Simultaneous determination of dasatinib, nilotinib, imatinib and its metabolite, CGP-74588, using ultra-violet high performance liquid chromatography (UV-HPLC).  Leukaemia Research 2010; 34: 702-707.

Dunwell T, Hesson L, Rauch T, Wang L, Clark RE, Dallol A, Gentle D, Catchpoole D, Maher ER, Pfeifer G, Latif F.  A Genome-wide screen identifies novel frequently methylated genes in leukemia and genes associated with clinical outcome in chronic myeloid leukaemia.  Molecular Cancer 2010; 9: 44-55.

Lucas CM, Harris RJ, Giannoudis A, Knight K, Watmough SJ, Clark RE.  BCR-ABL1 tyrosine kinase activity at diagnosis, as determined via the pCrKL/CrKL ratio, is predictive of clinical outcome in chronic myeloid leukaemia.  British Journal of Haematology 2010; 149: 458-460.

Burnett AK, Russell NH, Kell J, Dennis M, Milligan D, Baccarani M, Yin JL, Culligan D, Johnson P, Murphy J, McMullin M-F, Hunter A, Das-Gupta E, Clark RE, Carr R, Hills RK.  European development of clofarabine as treatment for older patients with acute myeloid leukaemia considered unsuitable for intensive chemotherapy.  Journal of Clinical Oncology 2010; 28: 2389-2395.

Boultwood J, Perry J, Zaman R, Fernandez-Santamaria C, Littlewood T, Kusec R, Pellagatti A, Wang L, Clark RE, Wainscoat JS.  High density single nucleotide polymorphism array analysis and ASXL1 gene mutation screening in chronic myeloid leukaemia during disease progression.  Leukemia 2010; 24: 1139-1145.

Saglio G, Kim D-W, Issaragrisil S, le Coutre P, Etienne G, Lobo C, Pasquini R, Clark RE, Hochhaus A, Hughes TP, Gallagher N, Hoenekopp A, Dong M, Haque A, Larson RA, Kantarjian HM.  ENESTnd: A randomized comparison of nilotinib and imatinib for newly diagnosed chronic myeloid leukemia.  New England Journal of Medicine 2010; 362: 2251-2259.

Lucas CM, Harris RJ, Giannoudis A, Clark RE.  SET (I2PP2A) binding protein 1 expression does not predict clinical outcome in chronic myeloid leukaemia.  eBlood, 4th April 2010 [letter].

Rojas JM, Knight K, Watmough S, Bell J, Wang L, Callaghan T, Clark RE.  BCR-ABL peptide vaccination in healthy subjects: immunological responses are equivalent to those in chronic myeloid leukaemia patients.  Leukemia Research 2010; **epub June 21st 2010**.  

Chakraverty R, Orti G, Roughton M, Shen J, Fielding A, Kottaridis P, Milligan D, Collin M, Crawley C, Roddie H, Clark A, Parker A, Liakopoulou E, Pettengel R, Snowden J, Pettitt A, Clark RE, Hale G, Peggs K, Thomson K, Morris E, Mackinnon S.  Impact of in vivo alemtuzumab dose before reduced intensity conditioning and HLA-identical sibling stem cell transplantation: pharmacokinetics, GVHD and immune reconstitution.  Blood 2010; **epub June 29th 2010**.

Grant H, Stebbing J, Foroni L, Craddock C, Griffiths M, Clark RE, O’Brien S, Khorashad JS, Gerrard G, Wang L, Irving JAE, Wang M, Karran EL, Dyer MJS, Eaves CJ, Page K, Jiang X, Woolfson A.  Analysis of BCR-ABL1 tyrosine kinase domain mutational spectra in primitive chronic myeloid leukemia cells identifies a unique mutator phenotype.  Leukemia 2010; **epub August 26th 2010**.

Giles FJ, Rosti G, Beris P, Clark RE, le Coutre P, Mahon F-X, Steegmann J-L, Valent P, Saglio G.  Nilotinib is superior to imatinib as first line therapy of chronic myeloid leukemia (CML): the ENESTnd study as a landmark on the path to cure in CML.  Expert Reviews in Haematology, ** accepted 25 August 2010**.

Estabragh ZR, Knight K, Watmough SJ, Lane S, Vinjamuri S, Hart G, Clark RE.  A prospective evaluation of cardiac function in chronic myeloid leukaemia treated with imatinib.  **Leukemia Research, accepted 27th August 2010**, doi:10.1016/j.leukres.2010.08.020. 

Rojas JM, Wang LH, Owen S, Knight K, Watmough S, Clark RE.  Naturally occurring CD4+ CD25+ FOXP3+ T regulatory cells are increased in chronic myeloid leukaemia patients with high BCR-ABL transcripts and can suppress anti-BCR-ABL responses.  **Experimental Hematology, accepted 2nd September 2010**. 

Daghistani M, Marin D, Khorashad JS, May PC, Paliompeis C, Milojkovic D, De Melo VA, Clark RE, Holyoake TL, Gerard G, Goldman JM, Apperley JF, Foroni L, Reid AG.  EVI-1 oncogene expression predicts survival in chronic phase CML patients resistant to imatinib.  **Blood 2010; accepted 10th September**.

Clark RE (2008). 
Immunotherapy in Chronic Myeloid Leukaemia. 
In Mughal TI and Goldman JM; editors; Recent advances in the Chronic Myeloproliferative Disorders.
Informa Health Care, London. p118-125.

Dodi IA, Rusakiewicz S, Aubert G, Clark RE, Creaser C, Bonner P, Rees R, Travers PJ, Madrigal JA (2007).  Definition of the breakpoint fusion peptides for HLA-B8 as well as HLA-A3 in CML cells. 
Immunobiology of the Human MHC; proceedings of 13th International workshop and congress  vol II.  Ed Hansen JA. International Histocompatibility Working Group Publishing, Seattle, p 275-280; 2007.

Clark RE (2005). 
The immune response to chronic myeloid leukaemia. 
In "Focus on Leukemia Research", ed. Rafael F Romero, Nova Science Publishers, Inc., New York, p27-60.

RE Clark
Molecular and Clinical Cancer Medicine
0151 706 4323
R.E.Clark@liverpool.ac.uk