A bioinformatic approach to mesothelioma therapeutics: from ADAM to TRAP
Arginine deprivation is a novel antimetabolite strategy for the treatment of arginine-dependent cancers that exploits differential expression and regulation of key urea cycle enzymes. Several studies have focused on inactivation of argininosuccinate synthetase 1 (ASS1) in a range of malignancies, including melanoma, hepatocellular carcinoma, and mesothelioma. Promoter methylation, in particular, has been identified as a mechanism for loss of the tumor suppressor role of ASS1 leading to tumoral dependence on exogenous arginine. Clinical trials of several arginine depletors are ongoing, including pegylated arginine deiminase (ADI-PEG20, Polaris Group, US) and bioengineered forms of human arginase. The challenge will be to identify tumors sensitive to arginine depletors, and integrate these agents into multimodality drug regimens using predictive biomarkers. Here, we have applied a bioinformatic approach to identify tractable pathways with ADI-PEG20 in the treatment of patients with mesothelioma. Recently, our phase 2 study of ADI-PEG20 in mesothelioma (ADAM) completed accrual and we are now launching a phase I combinatorial trial (TRAP) in the UK based on our bioinformatics studies.
Dr Peter Szlosarek (MBBS BSc MRCP PhD) is a Clinical Senior Lecturer at the Barts Cancer Institute, and Cancer Physician at St. Bartholomew’s Hospital, London. He studied Medicine and Pharmacology at King’s College, London and then specialised in Medical Oncology completing a PhD on the links between TNF-a, inflammation and cancer at the University of London. His clinical and lab research interests are in metabolic approaches to cancer therapy, particularly the role of arginine deprivation therapy in arginine-dependent cancers. This has led to clinical trials of the arginine-depleting agent ADI-PEG20 (Polaris Group, US) in mesothelioma (CTAAC grant) and small cell lung cancer, the latter a collaboration with the Ludwig Institute for Cancer Research in New York, US. He is funded by several grant bodies including Cancer Research UK, Barts and The London Charity, Medical Research Council and the British Lung Foundation. He maintains a research-orientated clinical practice at Barts in thoracic and cutaneous malignancy and is a member of the Royal College of Physicians, the Association of Cancer Physicians, the EORTC, AACR and ASCO.