Targeting arginine-dependent cancers with arginine-degrading enzymes: opportunities and challenges.
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 (HCC), mesothelial and urological cancers, sarcomas, and lymphomas. Epigenetic silencing has been identified as a key mechanism for loss of the tumor suppressor role of ASS1 leading to tumoral dependence on exogenous arginine. More recently, dysregulation of argininosuccinate lyase has been documented in a subset of arginine auxotrophic glioblastoma multiforme, HCC and in fumarate hydratase-mutant renal cancers. Clinical trials of several arginine depletors are ongoing, including pegylated arginine deiminase (ADI-PEG20, Polaris Group) and bioengineered forms of human arginase. ADI-PEG20 is furthest along the path of clinical development from combinatorial phase 1 to phase 3 trials and is described in more detail. The challenge will be to identify tumors sensitive to drugs such as ADI-PEG20 and integrate these agents into multimodality drug regimens using imaging and tissue/fluid-based biomarkers as predictors of response. Lastly, resistance pathways to arginine deprivation require further study to optimize arginine-targeted therapies in the oncology clinic.
Center for Molecular Oncology, Barts Cancer Institute - a Cancer Research UK Centre of Excellence, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, UK. ; St Bartholomew's Hospital, London, UK.
Melissa M
MM
Phillips
Pathology Group, Institute of Cell and Molecular Sciences, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, UK.
Michael T
MT
Sheaff
Center for Molecular Oncology, Barts Cancer Institute - a Cancer Research UK Centre of Excellence, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, UK. ; St Bartholomew's Hospital, London, UK.
Peter W
PW
Szlosarek
ADI-PEG20; Arginase; Arginine; Argininosuccinate lyase; Argininosuccinate synthetase; Drug combinations; Neoplasms