Medicine

Simon Crabb

BSc, MBBS, MRCP, PhD

Primary position:
Senior Lecturer in Medical Oncology

Background

The University of Southampton

Dr Crabb was appointed as a Senior Lecturer in Medical Oncology in 2009. Having graduated in medicine from St George’s Hospital, London in 1996 he joined the University of Southampton in 2002 as a Cancer Research UK Clinical Research Fellow and a member of Professor Graham Packham’s group. He was awarded his PhD in 2006 for work involving the development and characterisation of novel histone deacetylase inhibitors. Following a Clinical Research Fellowship at the BC Cancer Agency in Vancouver, he returned to the Cancer Sciences Division as a Clinical Lecturer and completed higher specialist training as a Medical Oncologist in 2008.

Dr Crabb’s work is divided between the laboratory and the Department of Medical Oncology at University Hospital Southampton NHS Foundation Trust where he specialises in the management of genitourinary cancers and holds an Honorary Consultant post. His laboratory research interests are in epigenetic therapeutic agents, mechanisms of chemotherapy resistance and the development of molecularly targeted therapeutic strategies for genitourinary cancers. He is also active in clinical trials and involved in a number of early phase trials for genitourinary cancers.

Qualifications

BSc, Biochemistry, University of London, 1993
MBBS, Medicine, University of London, 1996
MRCP, Royal College of Physicians, 2000
PhD, University of Southampton, 2006

Appointments held

Senior Lecturer in Medical Oncology, University of Southampton Faculty of Medicine

Honorary Consultant in Medical Oncology, University Hospital Southampton NHS Foundation Trust

Dr Simon Crabb's photo

Publications

The University of Southampton's electronic library (e-prints)

Article

Pienta, Kenneth J., Machiels, Jean-Pascal, Schrijvers, Dirk, Alekseev, Boris, Shkolnik, Mikhail, Crabb, Simon J., Li, Susan, Seetharam, Shobha, Puchalski, Thomas A., Takimoto, Chris, Elsayed, Yusri, Dawkins, Fitzroy and de Bono, Johann S. (2012) Phase 2 study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 (CCL2), in metastatic castration-resistant prostate cancer. Investigational New Drugs (doi:10.1007/s10637-012-9869-8). (PMID:22907596).
Crabb, Simon J., Bradbury, J., Nolan, L., Selman, D., Muthuramalingam, Sethupathi R., Cave, Judith, Johnson, Peter W.M. and Ottensmeier, Christian (2012) A phase I clinical trial of Irinotecan and Carboplatin in patients with extensive stage small cell lung cancer. Chemotherapy, 58, (4), 257-263. (doi:10.1159/000341274). (PMID:22907396).
Crabb, Simon J., Bradbury, Jennifer, Nolan, Luke, Selman, Diana, Muthuramalingam, Sethupathi R., Cave, Judith, Johnson, Peter W.M. and Ottensmeier, Christian (2012) A phase I clinical trial of irinotecan and carboplatin in patients with extensive stage small cell lung cancer. Chemotherapy, 58, (4), 257-263. (doi:10.1159/000341274). (PMID:22907396).
Powles, Thomas, Sarwar, Naveed, Jones, Rob, Wilson, Peter, Boleti, Ekaterini, Protheroe, Andrew, Crabb, Simon J, Shamash, Jonathan, Stockdale, Andrew, Rashid, Sukaina, Nathan, Paul and Chowdury, Simon (2012) An indirect comparison of the toxicity of sunitinib and pazopanib in metastatic clear cell renal cancer. European Journal of Cancer (doi:10.1016/j.ejca.2012.05.022). (PMID:22766517).
Hayden, Annette, Johnson, Peter W.M., Packham, Graham and Crabb, Simon J. (2011) S-adenosylhomocysteine hydrolase inhibition by 3-deazaneplanocin A analogues induces anti-cancer effects in breast cancer cell lines and synergy with both histone deacetylase and HER2 inhibition. Breast Cancer Research and Treatment, 127, (1), 109-119. (doi:10.1007/s10549-010-0982-0). (PMID:20556507).
Benelkebir, Hanae, Marie, Sabrina, Hayden, Annette L., Lyle, Jason, Loadman, Paul M, Crabb, Simon J., Packham, Graham and Ganesan, A. (2011) Total synthesis of largazole and analogues: HDAC inhibition, antiproliferative activity and metabolic stability. Bioorganic & Medicinal Chemistry (doi:10.1016/j.bmc.2011.02.024). (PMID:21420302).
Benelkebir, Hanae, Hodgkinson, Christopher, Duriez, Patrick J., Hayden, Annette L., Bulleid, Rosemary A., Crabb, Simon J., Packham, Graham and Ganesan, A. (2011) Enantioselective synthesis of tranylcypromine analogues as lysine demethylase (LSD1) inhibitors. Bioorganic & medicinal chemistry (doi:10.1016/j.bmc.2011.02.017). (PMID:21382717).
Crabb, Simon J. and Wheater, Matthew J. (2010) Advances in chemotherapy and targeted systemic therapies for Urothelial cancer. Current Drug Therapy, 5, (1), 17-28.
Ganesan, A., Nolan, L., Crabb, S.J. and Packham, G. (2009) Epigenetic therapy: histone acetylation, DNA methylation and anti-cancer drug discovery. Current Cancer Drug Targets, 9, (8), 963-981.
Sharp, Adam, Crabb, Simon J., Johnson, Peter W.M., Hague, Angela, Cutress, Ramsey, Townsend, Paul A., Ganesan, A. and Packham, Graham (2009) Thioflavin S (NSC71948) interferes with Bcl-2-associated athanogene (BAG-1)-mediated protein-protein interactions. Journal of Pharmacology and Experimental Therapeutics, 331, (2), 680-689. (doi:10.1124/jpet.109.153601).
Crabb, S.J., Patsios, D., Sauerbrei, E., Ellis, P.M., Arnold, A., Goss, G., Leighl, N.B., Shepherd, F.A., Powers, J., Seymour, L. and Laurie, S.A. (2009) Tumor cavitation: impact on objective response evaluation in trials of angiogenesis inhibitors in non-small-cell lung cancer. Journal of Clinical Oncology, 27, (3), 404-410. (doi:10.1200/JCO.2008.16.2545).
Nolan, L., Johnson, P.W.M., Ganesan, A., Packham, G. and Crabb, S.J. (2008) Will histone deacetylase inhibitors require combination with other agents to fulfil their therapeutic potential? British Journal of Cancer, 99, 689-694. (doi:10.1038/sj.bjc.6604557).
Crabb, S.J., Howell, M., Rogers, H., Ishfaq, M., Yurek-George, A., Carey, K., Pickering, B.M., East, P., Mitter, R., Maeda, S., Johnson, P.W.M., Townsend, P., Shin-Ya, K., Yoshida, M., Ganesan, A. and Packham, G. (2008) Characterisation of the in vitro activity of the depsipeptide histone deacetylase inhibitor spiruchostatin. Biochemical Pharmacology, 76, (4), 463-475. (doi:10.1016/j.bcp.2008.06.004). (PMID:18611394).
Crabb, Simon J., Hague, Angela, Johnson, Peter W.M. and Packham, Graham (2008) BAG-1 inhibits PPARgamma-induced cell death, but not PPARgamma-induced transcription, cell cycle arrest or differentiation in breast cancer cells. Oncology Reports, 19, (3), 689-696.
Crabb, S.J., Bajdik, C.D., Leung, S., Speers, C.H., Kennecke, H, Huntsman, D.G. and Gelmon, K.A. (2008) Can clinically relevant prognostic subsets of breast cancer patients with four or more involved axillary lymph nodes be identified through immunohistochemical biomarkers? A tissue microarray feasibility study. Breast Cancer Research, 10, (1) (doi:10.1186/bcr1847). (PMID:18194560).
Crabb, S.J., Cheang, M.C., Leung, S, Immonen, T, Nielsen, T.O., Huntsman, D.D., Bajdik, C.D. and Chia, S.K. (2008) Basal breast cancer molecular subtype predicts for lower incidence of axillary lymph node metastases in primary breast cancer. Clinical Breast Cancer, 8, (3), 249-256. (doi:10.3816/CBC.2008.n.028).
Ryan, G., Martinelli, G., Kuper-Hommel, M., Tsang, R., Pruneri, G., Yuen, K., Roos, D., Lennard, A., Devizzi, L., Crabb, S., Hossfeld, D., Pratt, G., Dell'Olio, M., Choo, S.P., Bociek, R.G., Radford, J., Lade, S., Gianni, A.M., Zucca, E., Cavalli, F. and Seymour, J.F. (2008) Primary diffuse large B-cell lymphoma of the breast: prognostic factors and outcomes of a study by the International Extranodal Lymphoma Study Group. Annals of Oncology, 19, (2), 233-241. (doi:10.1093/annonc/mdm471).
Lee, San San, Crabb, Simon J., Janghra, Nari, Carlber, Carsten, Williams, Ann C., Cutress, Ramsey I., Packham, Graham and Hague, Graham (2007) Subcellular localisation of BAG-1 and its regulation of vitamin D receptor-mediated transactivation and involucrin expression in oral keratinocytes: Implications for oral carcinogenesis. Experimental Cell Research, 313, (15), 3222-3238. (doi:10.1016/j.yexcr.2007.06.010).
Sharp, Adam, Crabb, Simon J., Cutress, Ramsey I., Brimmell, Matthew, Wang, Xiu-hong, Packham, Graham and Townsend, Paul A. (2004) BAG-1 in carcinogenesis. Expert Reviews in Molecular Medicine, 6, (7), 1-15. (doi:10.1017/S1462399404007537). (PMID:15033003).
Crabb, S.J., McKendrick, J.J. and Mead, G.M. (2002) Brain as sanctuary site of relapse in germ cell cancer patients previously treated with chemotherapy. Clinical Oncology, 14, (4), 287-293. (doi:10.1053/clon.2002.0075).
Tate, A R, Crabb, S, Griffiths, J R, Howells, S L, Mazucco, R A, Rodrigues, L M and Watson, D (1996) Lipid metabolite peaks in pattern recognition analysis of tumour in vivo MR spectra. Anticancer research, 16, (3B), 1575-9. (PMID:8694529).

Book Section

Cutress, Ramsay I., Crabb, S.J., Sharp, A., Townsend, P.A. and Packham, G. (2007) The significance and function of BAG-1 in breast cancer. In, Yao, Andrew P. (ed.) New Developments in Breast Cancer Research. USA, Nova Science, 1-30. (Horizons in Cancer Research, 23).
 

Research

Research Interests

Dr Crabb’s research group is interested in developing new therapeutic options for genitourinary and other malignancies. In addition he is actively involved in a number of clinical trials for genitourinary cancer and a member of national clinical trials groups for prostate and bladder cancer.

Epigenetic Therapeutics

In addition to abnormalities of DNA sequence, complex epigenetic abnormalities are also recognised to underpin cancer development. Epigenetic abnormalities are attractive therapeutic targets as they may potentially be amenable to direct correction through inhibition of their enzymatic mediators. Dr Crabb is interested in the development of therapeutic agents to target epigenetic processes in cancer.

Previous work has involved investigation of novel histone deacetylase (HDAC) inhibitors. A detailed characterisation of the in vitro activity of spiruchostatin A was undertaken in collaboration with colleagues in the Department of Chemistry in Southampton. Spiruchostatin A is a depsipeptide natural product with close structural similarities to the HDAC inhibitor vorinostat which is currently being evaluated in clinical trials for a variety of cancers. Results demonstrated that spiruchostatin A is a potent inhibitor of class I HDACs. Differences in the kinetics of biological action of different HDAC inhibitor structural classes were demonstrated which may be important for the future clinical application of these compounds.

More recently this group has undertaken investigation of agents to target histone methylation as a therapeutic strategy. For example, the histone methyltransferase enhancer of zeste homolog 2 (EZH2) is over-expressed and linked to poor prognosis in many cancers including prostate, breast and bladder cancer. Dr Crabb’s group have assessed inhibition of EZH2 function in breast cancer using the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin (DZNep) and a number of structural analogues as experimental chemical inhibitors. This approach was found to induce cell cycle arrest and apoptosis. Combination approaches using DZNep analogues with both epigenetic and other targeted agents for breast cancer (HDAC inhibition and HER2 inhibition respectively) induced synergistic effects on breast cancer cell proliferation. This works establishes the principle that histone methylation is a therapeutic target worthy of further investigation and the group are extending this approach to prostate and bladder cancer.

Further work is looking at the histone demethylase enzyme LSD1. Work is currently ongoing to establish the value of chemical inhibition of this enzyme which mediates androgen receptor function in prostate cancer.

Mechanisms of Chemotherapy Resistance in Bladder Cancer

The group is investigating mechanisms for the development of chemotherapy resistance in bladder and other cancers. The transcription factor Nrf2 controls expression of multiple target genes, each containing an antioxidant response element. These targets mediate cellular protection through antioxidant response, cellular detoxification (including glutathione conjugation) and altered drug uptake/efflux. Some Nrf2 targets (e.g. metallothionein, glutathione reductase) are associated with bladder cancer characteristics, outcomes and chemotherapy resistance. Nrf2 regulation is partially understood and includes negative regulation by Keap1 and phosphorylation. De-novo or acquired cisplatin resistance is a problem in bladder cancer. Ongoing work is testing the hypothesis that Nrf2 is a mediator in part of cisplatin resistance in bladder cancer and potential means to reverse it therapeutically that might then be amenable to clinical testing.

Molecularly Targeted Therapeutic Strategies for Bladder Cancer

Dr Crabb’s work is looking at the potential to target the human epidermal growth factor receptor (HER) family in bladder cancer. The HER family are cell surface tyrosine kinase receptors which include the epidermal growth factor receptor (EGFR, HER1), HER2, HER3 and HER4. Aberrant HER family activation of downstream signaling pathways results in multiple biological effects in cancer cells including increased cellular proliferation, migration, attenuation of apoptosis, invasion and metastasis. Both EGFR and HER2 are over-expressed in a proportion of bladder cancers and relationships have been demonstrated between increased expression and tumour grade, tumour stage and survival outcomes. Drugs targeting EGFR and/or HER2 are in clinical trials for bladder cancer. The group’s interests are in understanding the degree to which co-inhibition of these receptors and downstream pathways will be required for them to be used as a therapeutic strategy in this disease and in the elucidation of resistance mechanisms to such strategies.

Academic unit:  Cancer Sciences

Responsibilities

Post Doctoral Supervision

Dr Annette Hayden

Doctoral Student Supervision

Current

Regina Mora Vidal
James Douglas

National Responsibilities

Chemotherapy Subgroup member of the National Cancer Research Network Bladder Cancer Clinical Studies Group
Castration Resistant Prostate Cancer Subgroup member of the National Cancer Research Network Prostate Cancer Clinical Studies Group

Teaching Responsibilities

BM5 and BM4. Provides clinical teaching to all years, based at Southampton General Hospital

Head of Field for Oncology for BMedSc projects.

Contact

Dr Simon Crabb
Faculty of Medicine
University of Southampton
Southampton General Hospital
Mailpoint 801
South Academic Block
Tremona Road
Southampton
SO16 6YD
or
Faculty of Medicine
University of Southampton
Building 85
Life Sciences Building
Highfield Campus
Southampton
SO171BJ

Room Number: SGH/CSB/MP824

Telephone: (023) 8120 5170
Facsimile: (023) 8120 5152
Email: S.J.Crabb@southampton.ac.uk