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.
CONFIRM trial: what is the real efficacy of second-line immunotherapy in mesothelioma? – Authors' reply Fennell DA, Griffiths G, Ottensmeier C et al. The Lancet Oncology (2022) 23(7) e14-e15
Priming Death Receptor Mediated Apoptosis with Arginine Starvation Sensitises Arginine Auxotrophic B-ALL to CAR-T Austin MJ, Halim L, Miraki-Moud F et al. Blood (2021) 138(10) 2787-2787
Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial Fennell DA, Ewings S, Ottensmeier C et al. The Lancet Oncology (2021) 22(7) 1530-1540
Phase 1, pharmacogenomic, dose-expansion study of pegargiminase plus pemetrexed and cisplatin in patients with ASS1-deficient non-squamous non-small cell lung cancer Szlosarek PW, Wimalasingham AG, Phillips MM et al. Cancer Medicine (2021) 10(7) 6642-6652
Nivolumab Versus Placebo in Relapsed Malignant Mesothelioma: The CONFIRM Phase 3 Trial Fennell D, Ottensmeier C, Califano R et al. JOURNAL OF THORACIC ONCOLOGY (2021) 16(11) S62-S62
PS01.11 Nivolumab Versus Placebo in Relapsed Malignant Mesothelioma: The CONFIRM Phase 3 Trial Fennell D, Ottensmeier C, Califano R et al. Journal of Thoracic Oncology (2021) 16(10) s62
Phase 1b study of pegylated arginine deiminase (ADI-PEG 20) plus Pembrolizumab in advanced solid cancers Chang KY, Chiang NJ, Wu SY et al. OncoImmunology (2021) 10(7)
Expansion Phase 1 Study of Pegargiminase Plus Pemetrexed And Cisplatin in Patients With ASS1-Deficient Mesothelioma: Safety, Efficacy and Resistance Mechanisms Szlosarek PW, Phillips MM, Pavlyk I et al. JTO Clinical and Research Reports (2020) (1) 100093-100093
Abstract 2217: Pegylated arginine deiminase sensitizes ASS1-negative and KRAS mutant non-small cell lung cancer to PD-1 blockade immunotherapy Pavlyk I, Foster J, Dexter K et al. (2020) (10) 2217-2217
Phase II Study of Arginine Deprivation Therapy With Pegargiminase in Patients With Relapsed Sensitive or Refractory Small-cell Lung Cancer. Hall PE, Ready N, Johnston A et al. Clinical Lung Cancer (2020) 21(1) 527-533
Dr Iuliia Pavlyk
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.