Professor Peter Szlosarek
Group Leader
Overview
My main research interest is in exploring why ASS1 is aberrantly expressed in human cancers and how this knowledge may be exploited for anticancer therapy. I lead an active translational programme from bench to bedside of the arginine-depleting agent ADI-PEG20 in several hard-to-treat cancers including ADAM, TRAP and ATOMIC clinical studies.
Research
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 necessary for L-arginine synthesis, including: hepatocellular carcinoma, malignant melanoma, malignant pleural mesothelioma, glioma, 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, lymphoma and bladder cancer, that are sensitive to arginine deprivation.
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 conducted the first randomized trial of the arginine-lowering agent, pegylated arginine deiminase (ADI-PEG20, Polaris Pharma) in mesothelioma using ASS1 as a prospective biomarker showing an improvement in progression-free survival (Szlosarek et al, JAMA Oncol 2017). The current TRAP programme has reported potentiation of anti-folates by ADI-PEG20, which has now moved into phase 2/3 testing in a global trial in non-epithelioid mesothelioma called ATOMIC-meso. Further studies are planned of ADI-PEG20 in combination with immune checkpoint blockade based on exciting new data from the lab.
We continue to study the links between inflammation, immunity and metabolism to discover novel therapeutic targets in oncology.
Key Publications
Phase 1 dose-escalation study of pegylated arginine deiminase, cisplatin and pemetrexed in patients with argininosuccinate synthetase 1-deficient thoracic cancers. J Clin Onc (2017) 35 (16):1778-785. PMID: 28388291
Arginine Deprivation with Pegylated Arginine Deiminase in Patients with ASS1-Deficient Malignant Pleural Mesothelioma: A Randomized Clinical Trial. JAMA Oncol (2017)3(1):58-60. PMID: 27584578
Prognostic and therapeutic impact of argininosuccinate synthetase 1 control in bladder cancer as monitored longitudinally by PET imaging. Cancer Res (2014) 74(3):896-907. PMID: 24285724
In vivo loss of expression of argininosuccinate synthetase in malignant pleural mesothelioma is a biomarker for susceptibility to arginine depletion. Clin Cancer Res (2006) 12(23):7126-31. PMID: 17145837
See recent publicationsMajor Funding
- 2019-2021- Barts Charity, Targeting the stromal compartment of ASS1-deficient mesothelioma, £149,994
- ATOMIC-meso (Polaris Pharma) and iTRAP (Polaris Pharma/Roche UK) commercial funding
Other Activities
- Chair of the NCRI mesothelioma subgroup
- EORTC lung and melanoma groups
- Reviewer for national and international journals
- Grant reviewer for national and international funding agencies
Biography
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-α 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 arginine metabolism and inflammation and is closely allied to my clinical interests in the treatment of mesothelial, lung and skin cancers.
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Clinical trial shows tumour-starving drug improves survival of mesothelioma
An innovative therapy provides new hope to patients with malignant mesothelioma – a rare but rapidly fatal type of cancer with few effective treatment options – according to results presented by Professor Peter Szlosarek and his team at Barts Cancer Institute, Queen Mary University of London.
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Investigating new treatment options for mesothelioma
Results from a phase I clinical trial led by Professor Peter Szlosarek were recently published in JTO Clinical and Research Reports. The trial was investigating the safety and efficacy of a new drug combination for the treatment of mesothelioma. We spoke to Professor Szlosarek to find out more about the trial, and how the drug combination may be able to help patients with mesothelioma.
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Therapy for high-grade glioma
A phase I clinical trial that set out to assess the safety of a new combination therapy for a type of aggressive brain tumour has found the treatment to be well tolerated in patients. The trial used a treatment combination of ADI-PEG20, pemetrexed and cisplatin, which showed encouraging efficacy in patients with recurrent high-grade gliomas (HGGs), a disease for which little progress has been made over the last few decades.
General News 2 April 2019