Dr Peter Szlosarek

MD, PhD
Centre: Molecular Oncology
Clinical Senior Lecturer
This email address is being protected from spambots. You need JavaScript enabled to view it.

QMUL Directory


My main research interest is in exploring why argininosuccinate synthetase (ASS1), a rate-limiting enzyme in L-arginine synthesis, is aberrantly expressed in human cancers.

 

Research Details

Arginine, a semi-essential amino acid in humans, is critical for the growth of human cancers, particularly those marked by de novo chemoresistance and a poor clinical outcome. In addition to protein synthesis, arginine is involved in diverse aspects of tumour metabolism, including the synthesis of nitric oxide, polyamines, nucleotides, proline and glutamate.

However, several tumours are unable to produce arginine, due to variable loss of the enzyme argininosuccinate synthetase ASS1, which is necesary for L-arginine synthesisis. Including: hepatocellular carcinoma, malignant melanoma, malignant pleural mesothelioma, prostate and renal cancer.

Our lab is exploring why ASS1 is aberrantly expressed in human cancers. We have identified methylation-dependent silencing of ASS1 in several tumours, including mesothelioma, ovarian cancer and lymphoma, that are sensitive to arginine deprivation.  We are now testing whether the ASS1-deficiency of mesothelioma may be exploited using the arginine-lowering agent, pegylated arginine deiminase (ADI-PEG20). Several phase I/II clinical trials of pegylated arginine deiminase have shown encouraging evidence of clinical benefit and low toxicity in patients with ASS1-negative tumours.

Preclinical work in the area of arginine degradation is ongoing in several cancers with our national and international collaborators and industry. We are studying the regulation and modulation of ASS1 expression and the role of the proinflammatory microenvironment in arginine auxotrophic cancers, with the long-term aim of developing novel therapeutic strategies incorporating arginine deprivation and ASS1 loss into routine oncological practice.

We continue to study the links between inflammation and metabolism to discover novel therapeutic targets in oncology.

Profile

I graduated in 1994 from King’s College, London with degrees in Pharmacology, Medicine and Surgery, receiving the Pharmacology and Therapeutics Intercalated BSc Prize and Legg Prize in Surgical Pathology.

I obtained the MRCP in 1997, and subsequently trained in medical oncology at St. George's, Guy’s and St. Bartholomew's Hospitals, completing a PhD on the molecular biology of TNF- in ovarian cancer and a postdoctoral position in the Centre for Cancer and Inflammation under Prof Balkwill in 2005.

After a substantive NHS oncology consultant post, I rejoined the BCI as a Principal Investigator in 2008. My translational lab program focuses on aberrant tumour metabolism and inflammation and is closely allied to my clinical interests in the treatment of mesothelial, lung and skin cancers.

Funding

  • Cancer Research UK, Clinician Scientist Fellowship, 2008-2012, £1,026,479:  “Aberrant expression of argininosuccinate synthetase (ASS) and its therapeutic exploitation in human cancer”
  • Clinical Trials Advisory and Awards Committee (CTAAC), 2010-2012, £172, 580: “A Randomised Stratified Phase II Multicentre Clinical Trial of Single-agent ADI-PEG 20™ (Pegylated Arginine Deiminase) in Patients with Malignant Pleural Mesothelioma”
  • Barts and The London Charity, 2010-2011, £68, 341: “The role of arginine deprivation in the mesothelial tumour microenvironment”

Key Publications

Polo-like kinase 2 is an epigenetic determinant of chemosensitivity and candidate predictor of clinical outcome in ovarian cancer. Syed N, Coley HM, Sehouli J, Koensgen D, Mustea A, Szlosarek PW, McNeish I, Schmid P, Lovell DP, Blagden SP, Hatzimichael E, Crook T. Cancer Res. 2011. 71; 3317 PMID: 21402713

Arginine deprivation and argininosuccinate synthetase expression in the treatment of cancer. Delage B, Fennell DA, Nicholson L, McNeish I, Lemoine NR, Crook T, Szlosarek PW. Int J Cancer. 2010. 126:2762-72. PMID: 20104527

Epigenetic silencing of argininosuccinate synthetase confers resistance to platinum-induced cell death but collateral sensitivity to arginine auxotrophy in ovarian cancer. Nicholson LJ, Smith R, Hiller L, Szlosarek PW, Kimberley C, Sehouli J, Koensgen D, Mustea A, Schmid P, Crook T. Int J Cancer. 2009. 125: 1454-63. PMID: 19533750

Promoter hypermethylation of FANCF and outcome in advanced ovarian cancer. Lim SL, Smith P, Syed N, Coens C, Wong H, van der Burg M, Szlosarek P, Crook T, Green JA. Br J Cancer. 2008. 98: 1452-6. PMID: 18414472


Further Publications

For additional publications, please click here.


My main research interest is in exploring why argininosuccinate synthetase (ASS1), a rate-limiting enzyme in L-arginine synthesis, is aberrantly expressed in human cancers.

 

External Activities

Interview with LeighDay discussing causes and treatment of mesothelioma:

  • NCRI mesothelioma subgroup
  • EORTC lung and melanoma groups
  • Reviewer for national and international journals
  • Grant reviewer for national and international funding agencies

 

News


The Daily Express reported on our 2013 paper in Cancer Research showing that ADI-PEG20 therapy is effective, with minimal side-effects.

The multicentre ADI-PEG20 and Mesothelioma (ADAM) Trial is currently recruiting patients in the UK co-ordinated via the Barts CECM, in collaboration with BLT and Polaris Pharma., Inc: [Link]

We are also collaborating on several other arginine deprivation studies, including with the Ludwig Institute for Cancer Research and MSKCC in New York on a clinical trial of ADI-PEG20 in patients with small cell lung cancer, and with Polaris Pharma., Inc who is sponsoring a phase III clinical trial of ADI-PEG20 in liver cancer: [Link]

This site uses cookies in order to function properly. By continuing to browse, you agree that we can save them on your device. Privacy Policy.