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.
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
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.
A Phase I Study of Pegylated Arginine Deiminase (Pegargiminase), Cisplatin, and Pemetrexed in Argininosuccinate Synthetase 1-Deficient Recurrent High-grade Glioma. Hall PE, Lewis R, Syed N et al. Clin Cancer Res (2019) 25(2) 2708-2716
Current and Future Management of Malignant Mesothelioma: A Consensus Report from the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation. Tsao AS, Lindwasser OW, Adjei AA et al. J Thorac Oncol (2018) 13(2) 1655-1667
Rewiring urea cycle metabolism in cancer to support anabolism. Keshet R, Szlosarek P, Carracedo A et al. Nat Rev Cancer (2018) 18(2) 634-645
Rituximab in the treatment of pembrolizumab-induced myasthenia gravis. Crusz SM, Radunovic A, Shepherd S et al. Eur J Cancer (2018) 102(2) 49-51
CONFIRM: a double-blind, placebo-controlled phase III clinical trial investigating the effect of nivolumab in patients with relapsed mesothelioma: study protocol for a randomised controlled trial. Fennell DA, Kirkpatrick E, Cozens K et al. Trials (2018) 19(2) 233
Staging Uveal Melanoma with Whole-Body Positron-Emission Tomography/Computed Tomography and Abdominal Ultrasound: Low Incidence of Metastatic Disease, High Incidence of Second Primary Cancers. Cohen VML, Pavlidou E, DaCosta J et al. Middle East Afr J Ophthalmol (2018) 25(2) 91-95
Optimizing arginine deprivation for hard-to-treat cancers. Khadeir R, Szyszko T, Szlosarek PW Oncotarget (2017) 8(2) 96468-96469
A major responder to ipilimumab and nivolumab in metastatic uveal melanoma with concomitant autoimmunity. Chan PY, Hall P, Hay G et al. Pigment Cell Melanoma Res (2017) 30(1) 558-562
Phase 1 Dose-Escalation Study of Pegylated Arginine Deiminase, Cisplatin, and Pemetrexed in Patients With Argininosuccinate Synthetase 1-Deficient Thoracic Cancers. Beddowes E, Spicer J, Chan PY et al. J Clin Oncol (2017) 35(2) 1778-1785
Arginine Deprivation With Pegylated Arginine Deiminase in Patients With Argininosuccinate Synthetase 1-Deficient Malignant Pleural Mesothelioma: A Randomized Clinical Trial. Szlosarek PW, Steele JP, Nolan L et al. JAMA Oncol (2017) 3(2) 58-66
Mr Ramsay Khadeir
Clinical Research Fellows
Dr Matthew Mee, Dr Emily Turner
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.