Journal
CANCER RESEARCH AND TREATMENT
Volume 45, Issue 4, Pages 251-262Publisher
KOREAN CANCER ASSOCIATION
DOI: 10.4143/crt.2013.45.4.251
Keywords
Neoplasms; Arginine; Argininosuccinate synthetase; Argininosuccinate lyase; ADI-PEG20; Arginase; Drug combinations
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Funding
- British Lung Foundation [MRCCRTF11-8] Funding Source: researchfish
- Medical Research Council [G1001993] Funding Source: researchfish
- Medical Research Council [G1001993] Funding Source: Medline
- MRC [G1001993] Funding Source: UKRI
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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 hydratas-emutant 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.
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