Professor Freddie Charles Hamdy MD FRCSEd (Urol)

Academic Urology Unit
University of Sheffield
Royal Hallamshire Hospital
Glossop Road
Sheffield
S10 2JF

Tel: 44 (0)114 271 2154
Fax: 44 (0)114 271 2268

Secretary: Mrs Bex Bell

K130 Royal Hallamshire Hospital
Glossop Road
Sheffield
S10 2JF

Tel. 0114 271 2154
Fax 0114 271 2268

Professor of Urology

Freddie Hamdy qualified from the University of Alexandria, Egypt, in 1982. He completed his basic surgical training in the UK, and entered urological training in 1990. In 1993 he obtained his MD from the University of Sheffield, and was appointed Senior Lecturer at the University of Newcastle until 1998. During that time, he consolidated his clinical and research interest in uro-oncology. In 1999, he was appointed as founding Chair of Urology at the University of Sheffield, establishing the Academic Urology Unit. He received the Crystal Matula award from the European Association of Urology in 1996, and the Golden Telescope Award from the British Association of Urological Surgeons in 2002.

Research

Prostate Cancer Research Programme: The research activities of the Academic Urology Unit are based on two large clinical and basic science research programmes running in parallel. The group has been awarded grants from the Department of Health through its HTA panel (£14 million) to fund a multicentre randomised trial of case-finding and treatment in early prostate cancer; and from the National Cancer Research Institute (MRC, DoH, CRUK, £2.7 million), in partnership with a number of basic scientists in Sheffield and 5 other universities (Bristol, Cambridge, Manchester, Newcastle and York, and), to investigate mechanisms of disease progression. Work is focused on the management of early prostate cancer and investigation of a number of areas relevant to the biology of the disease, as follows:

• Molecular mechanisms of skeletal metastasis: (Collaboration with Prof P. Croucher, Bone Biology), using an integrated in vitro and in vivo approach to study simultaneously tumour cells (the seed) and the bony micro-environment (the soil). We are able to study individual genes of interest, their biological effect on metastasis and final effects on function in prostate cells.
• The role of proteases (Collaboration with Dr D.J. Buttle, Functional Genomics), and their inhibitors in prostate cancer: We have shown previously the importance of proteases and are determining the expression and role of these enzymes in prostate cancer progression and invasion, in particular the ADAMTS group of enzymes and some MMPs, which are implicated in shedding of receptors from cells.
• Angiogenesis, macrophage trafficking and PSA specific gene targeting: (Collaboration with Prof C. Lewis, Tumour Targeting Group, Prof N.J. Brown, Microcirculation Research Unit, and Prof N.j. Maitland, University of York). Macrophages concentrate in hypoxic areas in breast and prostate cancer and may prove to be suitable vehicles for targeted gene therapy. We are determining macrophage migration in vivo and investigating HIF-1/HIF-2 expression in prostate cancer, and assessing novel anti-angiogenic agents on progression of prostate cancer using direct injection versus established macrophage-based gene delivery systems of these agents in vivo.
• Genetic instability: (Collaboration with Prof M. Meuth and Dr A. Cox, Institute for Cancer Studies), investigating the role of DNA mismatch repair proteins, and apoptosis regulating genes in the development and progression of the disease, using molecular and genetic epidemiological approaches.
• Polycomb Group and Prostate Cancer: (Collaboration with Dr V. Cunliffe and Prof P. Ingham, Biomedical Sciences), study of the role of the Polycomb Group (PcG) of genes in the development and progression of prostate cancer. The joint project will shed new light on how PcG-mediated transcriptional silencing is involved in tumour progression in prostate cancer, using in vitro and in vivo model systems. The two groups are ideally placed for exciting interactions in elucidating some of the complex genetic abnormalities associated with prostate carcinogenesis.

Clinical Research:
The emphasis is on the ProtecT trial (Prostate testing for cancer and Treatment). Its aim is to test the effectiveness of treatment in early prostate cancer, through a case-finding programme and a randomised trial of treatment comparing monitoring, surgery and radiotherapy and their effect on survival from the disease at 10 years. 130,000 men will be tested, and approximately 3000 patients with prostate cancer will be diagnosed and investigated. The study will be an invaluable resource of material and data to complement ongoing translational work. We have full ethics approval to develop our biorepository of serum, blood, tissue and DNA extraction and storage from patients with prostate cancer as well as controls: (ProSPECT - Prostate SPEcimen Collection and sTorage) as part of our UK Prostate Cancer Collaborative network. In addition, an extension to the ProtecT study has been funded by CRUK to evaluate population-based screening in the UK, in parallel with treatment effectiveness.

Bladder Cancer Research Programme
Sheffield has a high prevalence of bladder cancer, reflecting the popularity of smoking and exposure to aromatic chemicals in the local coal, chemical and steel industries, within the region. Since 1999, a joint collaboration between the Academic Urology Unit (Mr J. Catto, Dr I. Rehman, Prof F.C. Hamdy), the Institute for Cancer Studies (Prof M Meuth) the Academic Pathology Unit (Dr S Cross) and Department of Pathology (Dr K Feeley) has focused on the basic science aspect and translational research in bladder cancer at Sheffield. This collaboration has resulted in the construction of a large bladder tumour biorepository (containing freshly frozen tumours with matching normal urothelium, blood and urine) and exploitation of the substantive bladder cancer bank (over 10,000 tumours) at the Royal Hallamshire Hospital's Department of Pathology.

Current Projects:

• Genomic Instability in Bladder Cancer: The extent and patterns of genomic instability in both bladder and upper tract transitional cell carcinomas (TCC) have been investigated. A contrasting pattern of microsatellite instability is seen in upper and lower tract TCC, in keeping with the distinct anatomical patterns seen in sporadic colorectal and gastric cancers. We have shown this is due to deficiency in the mismatch repair genes in the upper tract, but not in the bladder. Bladder TCCs show instability at solely tetranucleotide loci, the cause of which we are currently investigating.
• Hypermethylation in Bladder Cancer: We are using methylation specific PCR techniques to identify patterns of methylation in upper and lower tract TCC, and which genes are inactivated. Using methylation analysis, have epigenetically profiled 300 TCC. We will use the Affymetrix gene array facility to investigate the patterns of altered gene expression seen in low and high hypermethylator phenotype tumours. Candidate genes responsible for the regulation of DNA Methylation and histone acetylation will be investigated in this well-defined population of tumours.
• Use of Proteomic methods to find novel biomarkers in Bladder Cancer: Using 2D Proteomic Gels, differentially expressed proteins in normal urothelium and matching transitional cell tumours have been discovered. Using immunohistochemistry and western blotting, the expression of tumour specific proteins has been confirmed, and these are currently being investigated as novel diagnostic and prognostic biomarkers.
• Smoking and Chromosomal Instability in Bladder Cancer: In collaboration with Dr D. Hammond, Institute for Cancer Studies, we are investigating the effects of tobacco smoking on the pattern of Chromosomal Instability in TCC, using Comparative Genomic Hybridisation. We have found that the regions of chromosomal loss and gain differ according to patient's smoking exposure. Less regions of alteration are seen in the non-smoking population's tumours, suggesting the loci of the most important genes need for bladder carcinogenesis. We are currently confirming this work in a larger series of TCC, before searching for putative regulatory genes within these regions.
• Bio-Informatic approaches to the prediction of Bladder Cancer outcome: Additional molecular test are unlikely, on their own, to be 100% accurate for predicting tumour behaviour. Whilst a panel of biomarkers, genetically profiling tumours, is likely to improve the accuracy of tumour behaviour prediction, over current pathological grading and staging, an alternative method lies within data interpretation. We have shown that two artificial intelligence methods (Artificial Neural Networks and Neuro-Fuzzy Modelling (NFM)) can predict the behaviour of bladder cancer, more accurately than traditional statistical methods (see publications). The NFM approach is transparent and allows the importance of individual markers to be assessed. We are transferring and developing these techniques to prostate cancer and screening. We will also apply this modelling to the data from the Affymetrix gene arrays.

Principal funding sources

Clinical Research: HTA NHS R&D (jointly with the Universities of Bristol & Cambridge): the ProtecT study (Prostate testing for cancer & Treatment). Royal College of Surgeons of England: 3-D reconstruction of the prostate using transrectal ultrasound and image registration.

Laboratory & Translational Research: MRC/NCRI Strategic Grant on prostate cancer research (Collaborative grant with the Universities of Bristol, Cambridge, Manchester, Newcastle and York. British Urological Foundation (BUF) and Royal College of Surgeons of Edinburgh: mechanisms of skeletal metastases in prostate cancer (Research Training Fellowship for K. Linton); Engineering and Physical Sciences Research Council: with Medical Physics, Institute for Cancer Studies and the University of York: properties of urothelium. Medical Research Council: mismatch DNA repair gene expression and microsatellite instability in bladder cancer (Research Training Fellowship to JWF Catto). Yorkshire Cancer Research: macrophage trafficking in prostate cancer, co-investigator with Cellular and Molecular Pathology, and the University of York. Sheffield Hospitals Charitable Trust: A proteomic approach to the identification of novel prognostic markers in transitional cell carcinoma of the bladder. FP6, European Union: PRIMA (Prostate cancer Integral Management Approach): translational research Integrated Project. Partner and Bone Axis Research Co-ordinator. US Department of Defence: Investigation of DNA mismatch repair and apoptosis genes in prostate cancer.. Co-investigator, with Institute for Cancer Studies. CRUK: Evaluating population-based screening for localised prostate cancer in the UK: an extension to the ProtecT treatment trial, with the Universities of Bristol and Cambridge. Yorkshire Cancer Research: Co-investigator. The role of osteoprotegerin (OPG) in prostate cancer cell survival.

Recent Publications

Eaton CL, Wells, JM, Holen I, Croucher PI, Hamdy FC. "Serum Osteoprotegerin levels are associated with disease progression and response to androgen ablation in patients with prostate cancer." The Prostate (in press)

Catto JWF, Xinarianos G, Burton JL, Meuth M, Hamdy FC. (2003) "Differential expression of hMLH1 and hMSH2 is related to bladder cancer grade, stage and prognosis but not microsatellite instability." Int J Cancer 105(4):484-90

Hamdy FC. (2003) "Endothelin and skeletal metastases in hormone refractory prostate cancer." Eur Urol Suppl 2;3: 15-194.

Mills N, Donovan JL, Smith M, Jacoby A, Neal DE, Hamdy FC. (2003) "Patients' perceptions of equipoise are crucial to trial participation: a qualitative study of men in the ProtecT study." Controlled Clinical Trials; 24:272-2826.

Donovan J, Mills N, Smith M, Brindle L, Jacoby A, Peters T, Frankel S, Neal D, Hamdy FC. (2002) "Improving the design and conduct of randomised trials by embedding them in qualitative research: the ProtecT study." BMJ 325(7367):766-7010.

Holen I, Croucher PI, Hamdy FC, Eaton CL. (2002) "Osteoprotegerin (OPG) is a survival factor for human prostate cancer cells." Cancer Res 62:1619-2312.

Catto JWF, Linkens DA, Abbod MF, Chen M, Burton JL, Feeley K, Hamdy FC. (2003) "The application of artifical intelligence in predicting outcome of bladder cancer: a comparison of neuro-fuzzy modelling and artificial neural networks." Clin Cancer Res Sep 15;9(11):4172-4177.

Still K, Robson CN, Autzen P, Robinson MC, Hamdy FC. (2000) "Localisation and quantification of mRNA for matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) in human benign and malignant prostatic tissue." Prostate 42:18-2515.

Autzen P, Robson CN, Bjartell A, Malcolm AJ, Johnson MI, Neal DE, Hamdy FC. (1998) "Bone Morphogenetic protein-6 in skeletal metastases from prostate cancer and other common human malignancies." Br J Cancer 78:1219-1223.16.

Hamdy FC, Autzen P, Wilson Horne CH, Robinson MC, Neal DE, Robson CN. (1997) "Immunolocalization and mRNA expression of bone morphogenetic protein-6 in human benign and malignant prostate tissue." Cancer Res 57:4427-4431.