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Cancer Res Treat. 2013 Dec;45(4):251-62. doi: 10.4143/crt.2013.45.4.251. Epub 2013 Dec 31.

Targeting arginine-dependent cancers with arginine-degrading enzymes: opportunities and challenges.

Author information

  • 1Center 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.
  • 2Pathology Group, Institute of Cell and Molecular Sciences, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, UK.

Abstract

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.

KEYWORDS:

ADI-PEG20; Arginase; Arginine; Argininosuccinate lyase; Argininosuccinate synthetase; Drug combinations; Neoplasms

PMID:
24453997
[PubMed]
PMCID:
PMC3893322
Free PMC Article

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