Northern Institute for Cancer Research

Pharmacodynamic and mechanistic biomarkers

Pharmacodynamic and mechanistic biomarkers

About

Our work on pharmacodynamic biomarkers focuses on the development and validation of novel assays for use in a clinical trial setting, to determine the effects of anticancer drugs on the body.

Research Leaders

Alastair Greystoke
David Jamieson
Gareth Veal
Steve Wedge

Biomarker studies

We support clinical trials and cancer pharmacology research by investigating what drugs do to target tumour cells, in terms of their anticancer activity, as well as their impact on non-cancerous host cells, in terms of the toxicity associated with treatment.
A major challenge in this area is that we are only very rarely able to look in the cells that we are really interested in. For example, it is usually not feasible to obtain multiple biopsy samples to investigate the effect of a drug on tumour cells over a defined time period following its administration. Therefore we use surrogate tissues that can be taken from patients without the need for biopsies, commonly utilising blood as the most accessible and informative tissue.

Objectives

Objectives

These studies allow us to meet two key objectives, the prediction of efficacy and toxicity of chemotherapy and novel agents and the establishment of proof of mechanism for novel agents in early phase clinical trials.

Depending on the specific objective of the study we develop assays that analyse both cellular and non-cellular components of blood, including:

  • protein
  • Npnucleic acid (cfDNA, ctDNA, miRNA, germline DNA)
  • circulating tumour cells
  • rare haematopoietic cells

Publications

Margetts J, Ogle LF, Chan SL, Chan AWH, Chan KCA, Jamieson D, Willoughby CE, Mann DA, Wilson CL, Manas DM, Yeo W, Reeves HL. Neutrophils: driving progression and poor prognosis in hepatocellular carcinoma?. British Journal of Cancer 2018, 118, 248-257.

Jamieson D, Sunter N, Muro S, Pouché L, Cresti N, Lee J, Sludden J, Griffin MJ, Allan JM, Verrill MW, Boddy AV. Pharmacogenetic association of MBL2 and CD95 polymorphisms with grade 3 infection following adjuvant therapy for breast cancer with doxorubicin and cyclophosphamide. European Journal of Cancer 2017, 71, 15-24.

Jamieson D, Griffin MJ, Sludden J, Drew Y, Cresti N, Swales K, Merriman M, Allen R, Bevan P, Buerkle M, Mala C, Coyle V, Rodgers L, Dean E, Greystoke A, Banerji U, Wilson RH, Evans TRJ, Anthoney A, Ranson M, Boddy AV, Plummer R. A Phase I pharmacokinetic and pharmacodynamic study of the oral MEK inhibitor, WX-554, in patients with advanced solid tumours. European Journal of Cancer 2016, 68.

Cresti N, Lee J, Rourke E, Televantou D, Jamieson D, Verrill M, Boddy AV. Genetic variants in the HER2 gene: Influence on HER2 overexpression and loss of heterozygosity in breast cancer. European Journal of Cancer 2016, 55, 27-37.

Dent BM, Ogle LF, O'Donnell RL, Hayes N, Mallick U, Curtin NJ, Boddy AV, Plummer ER, Edmondson RJ, Reeves HL, May FEB, Jamieson D. High-resolution imaging for the detection and characterisation of circulating tumour cells from patients with oesophageal, hepatocellular, thyroid and ovarian cancers. International Journal of Cancer 2016, 138(1), 206-216.

Ogle LF, Orr JG, Willoughby CE, Hutton C, McPherson S, Plummer R, Boddy AV, Curtin NC, Jamieson D, Reeves HL. Imagestream detection and characterisation of circulating tumour cells - a liquid biopsy for hepatocellular carcinoma. Journal of Hepatology 2016, 65 (2), 305–313

Drew Y, Ledermann J, Hall G, Rea D, Glasspool R, Highley M, Jayson G, Sludden J, Murray J, Jamieson D, Halford S, Acton G, Backholer Z, Mangano R, Boddy A, Curtin N, Plummer R. Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly (ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer. British Journal of Cancer 2016, 114(7), 723-730.

Greystoke A, Hogarth L, Patterson M, Williams I, Ness T, Georgiadis K, Bolt L, Bettison I, Turner D, Jamieson D, Simmons T, Hughes A, Jaedicke K, Gardiner J, Mulvenna P, Leaning D, Bradshaw A, Butler R, Black F. The introduction of the Cancer Research UK Stratified Medicine Programme 2 (CRUK SMP2) in North East England; lessons learned and experience gained. In: 14th Annual British Thoracic Oncology Group Conference 2016. 2016, Dublin, Ireland: Elsevier.

Jamieson D, Lee J, Cresti N, Jackson R, Griffin M, Sludden J, Verrill M, Boddy AV. Pharmacogenetics of adjuvant breast cancer treatment with cyclophosphamide, epirubicin and 5-fluorouracil. Cancer Chemotherapy and Pharmacology 2014, 74(4), 667-674.

Hill CR, Jamieson D, Thomas HD, Brown CDA, Boddy AV, Veal GJ. Characterisation of the roles of ABCB1, ABCC1, ABCC2 and ABCG2 in the transport and pharmacokinetics of actinomycin D in vitro and in vivo. Biochemical Pharmacology 2013, 85(1), 29-37.

Jamieson D, Cresti N, Bray J, Sludden J, Griffin MJ, Hawsawi NM, Famie E, Mould EVA, Verrill MW, May FEB, Boddy AV. Two minor NQO1 and NQO2 alleles predict poor response of breast cancer patients to adjuvant doxorubicin and cyclophosphamide therapy. Pharmacogenetics and Genomics 2011, 21(12), 808-819.

Bray J, Sludden J, Griffin MJ, Cole M, Verrill M, Jamieson D, Boddy AV. Influence of pharmacogenetics on response and toxicity in breast cancer patients treated with doxorubicin and cyclophosphamide. British Journal of Cancer 2010, 102(6), 1003-1009.

Jamieson D, Cresti N, Verrill MW, Boddy AV. Development and validation of cell-based ELISA for the quantification of trastuzumab in human plasma. Journal of Immunological Methods 2009, 345(1-2), 106-111.