Clinical and Experimental Pharmacology (CEP)
The Remit and Organisation of the Clinical and Experimental Pharmacology Group
The goals of CEP are therefore (i) To spearhead early clinical evaluation of novel Mechanism Based Therapies by providing pharmacokinetic and innovative pharmacodynamic biomarker analyses to GCLP standards using state of the art technologies, and (ii) To respond to a national deficit in clinical and non-clinical translational pharmacology specialists by providing world class training for biomarker research in oncology. CEP was expanded significantly between 2004-2007 reflecting the breadth of its activities (in vitro, preclinical in vivo and clinical). A QA system was developed and implemented to meet the requirements of Good Clinical Laboratory Practice (GCLP) applied to clinical sample analyses where data have the potential to influence patient management. 2006 saw CEP move into purpose built, state of the art, translational laboratories at CRUK Manchester Institute.
Twin research themes within CEP are the evaluation of MBTs that promote tumour apoptosis (exploiting expertise of Professors Dive & Ranson) and those that prevent tumour angiogenesis (combining expertise in CEP with that of the adjacent collaborator Prof Gordon Jayson). The three Disease Focus Subgroups within CEP are lung cancer (led by Dr Fiona Blackhall), Colorectal Cancer (led by Mr Renehan) and Paediatric Cancers (led by Dr Guy Makin). CEP also extended its collaborations on biomarkers this year with clinical colleagues within MCRC (Prof Noel Clarke, GU cancers and Professors T Illidge and Radford, Haematological Malignancies).
CEP staff are organised into several teams, PD biomarkers, QA, PK, Clinical Proteomics and Biomarker Discovery, In vivo Pharmacology, and Molecular Pharmacology. Translational research studies include investigations of efficacy of novel drugs in hypoxic tumour cells (collaborating with Prof Ian Stratford and Dr Kaye Williams, School of Pharmacy, MCRC), and on optimal combinations and scheduling of novel with conventional therapeutics. Pre-clinically, CEP also develops and tests in vivo models with ‘switchable’ expression of drug targets or pathways. These models will facilitate the discovery of serological biomarkers, the development of tumour imaging tools with colleagues at the Wolfson Molecular Imaging Centre and evaluate on and off target effects of novel MBTs.
Training the Next Generation of Early Clinical Trialists
Training of translational scientists and academic pharmacologists (a national deficit): is achieved through a Clinical Pharmacology Fellowship Scheme for promising young doctors initiated in 2006. The Scheme is equally funded by CRUK and AstraZeneca leads to award of a PhD in Clinical and Experimental Pharmacology and has 2 Fellows in post and 2 recruited to start in 2007. The Fellows’ Projects are all biomarkers based and involve collaborations with many clinical colleagues within the MCRC. Fellows undertake their laboratory based research in CEP and elsewhere within MCRC and at AZ and attend one clinic per week in DCU.
Figure 1: Schematic of the workflow used for isolation and genetic analysis of individual CRC CTCs. Images are of 5 putative CTCs stained for cytokeratin (CK-PE) and DAPI. Sanger sequencing data obtained from each of the 5 putative CTCs and WBCs from the same patient is shown where red arrows indicate the location of the heterozygous PIKC3A mutation observed.