Dr Peter Szlosarek

MD, PhD
Centre: Molecular Oncology
Reader in Medical Oncology
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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 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 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 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.

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-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.

Funding

  • Polaris Pharma Industrial Grant, 2015-2018, TRAP Trial (Dr Szyszko, Mr Khadeir)
  • MRC, Clinical Research Fellowship (Dr Phillips) 2011-2015, £235,749, “The effect of tumour microenvironment on arginine deprivation in mesothelioma”
  • 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

Beddowes E1, Spicer J, Chan PY, Khadeir R, Garcia Corbacho J, Repana D, Steele JP, Schmid P, Szyszko T, Cook GJR, Diaz M, Feng X, Johnston A, Thomson J, Sheaff MT,Wu BW, Bomalaski J, Pacey S1, Szlosarek PW. Phase 1 dose-escalation study of pegylated arginine deiminase, cisplatin and pemetrexed in patients with argininosuccinate synthetase 1-deficient thoracic cancers. J Clin Onc 35(16):1778-785, 2017 PMID:28388291

Szlosarek PW, et al. Arginine Deprivation with Pegylated Arginine Deiminase in Patients with ASS1-Deficient Malignant Pleural Mesothelioma: A Randomized Clinical Trial. JAMA Oncol 3(1):58-60, 2017 PMID: 27584578

Locke M, Ghazaly E, Freitas MO, Mitsinga M, Lattanzio L, Lo Nigro C, Nagano A, Wang J, Chelala C, Szlosarek PW, Martin SA. Inhibition of the Polyamine Synthesis Pathway Is Synthetically Lethal with Loss of Argininosuccinate Synthase 1. Cell Reports 16(6):1604-13, 2016 PMID: 27452468

Karydis I, Chan PY, Wheater M, Arriola E, Szlosarek PW, Ottensmeier CH. Clinical activity and safety of Pembrolizumab in Ipilimumab pre-treated patients with uveal melanoma. Oncoimmunology 18;5(5):e1143997, 2016 PMID:27467964

Miraki-Moud F, Ghazaly E, Ariza-McNaughton L, Hodby KA, Clear A, Anjos-Afonso F, Liapis K, Grantham M, Sohrabi F, Cavenagh J,Bomalaski JS, Gribben JG, Szlosarek PW*, Bonnet D*, Taussig DC*. Arginine deprivation using pegylated arginine deiminase has activity against primary acute myeloid leukemia cells in vivo. Blood 125(26):4060-4068, 2016 PMID:25896651 [*joint last authors]

Allen M, Luong P, Hudson C, Leyton J, Delage B, Ghazaly E, Cutts R, Yuan M, Syed N, Lo Nior C, Lattanzio L, Chmielewska-Kassassir M, Tomlinson I, Roylance R, Whitaker HC, Warren AY, Neal D, Frezza C, Beltran L, Chelala C, Jones RL, Wu BW, Bomalaski JS, Jackson RC, Lu YJ, Crook T, Lemoine NR, Mather S, Foster J, Sosabowski J, Avril N, Li CF, Szlosarek PW. Prognostic and therapeutic impact of argininosuccinate synthase-1 control in bladder cancer as monitored longitudinally by PET imaging. Cancer Res 74(3):896-907, 2014 PMID:24285724


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 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.

 

External 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

 

News

  • June 2016: TRAP Trial progresses to Phase II/III Study ATOMIC-meso (ADIPEMCIS vs PEMCISPlacebo) for patients with biphasic and sarcomatoid mesothelioma. The trial opened in the UK in July 2017 and is currently recruiting patients globally (Europe, North America, Asia and Australia).
  • The multicentre TRAP Trial is currently recruiting patients in the UK led by the Barts ECMC, in collaboration with Cambridge ECMC and GKT ECMC with Polaris Pharma., Inc as sponsor. NSCLC (Beddowes et al), Uveal Melanoma, Glioma and Sarcomatoid Cohorts.
  • Further ADI-PEG20 trials are planned in combination with immune checkpoint blockade in a range of cancers including iTRAP and ATOMIC-B, based on novel data in the lab to be presented at the World Conference on Lung Cancer, Yokohama, Japan, 2017).
  • A phase 2 trial of ADI-PEG20 is planned for 2018 targeting high-grade glioma (ATOMIC-G).
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