Argininosuccinate synthetase 1 (ASS1) is an enzyme which is necessary for arginine synthesis.
‘Arginine dependency in bladder cancer may be a useful mechanism to selectively target a subset of these cancers using arginine-degrading enzyme or ADI-PEG 20.’
Arginine is a semi-essential amino acid that is synthesized from citrulline in two steps of the urea cycle. First step involves the conversion of citrulline and aspartate to argininosuccinate via the enzyme ASS1. The argininosuccinate is then converted to arginine and fumarate.
Arginase and arginine deiminase (ADI) are arginine-degrading enzymes. ADI-PEG 20 is a commercial formulation of arginine deiminase (ADI). It has a longer pharmacokinetic half-life.
Patients with tumors having low ASS1 expression have shorter survival. More than 90% of all bladder cancers are deficient in ASS1 and with few treatment options available to patients with advanced bladder cancer, researchers are looking for novel molecular targets.
"There is a major unmet need to identify additional therapies for bladder cancer patients that includes agents that can target both conventional urothelial carcinoma and less common subtypes of bladder cancer. Our findings suggest that arginine dependency in bladder cancer may be a useful mechanism to selectively target a subset of these cancers using ADI-PEG 20, although further investigation into the mediators of this effect and the role of combination therapy, including chemotherapy, to enhance efficacy is required," explained lead investigator Donna Hansel, MD, PhD, Professor of Pathology, University of California at San Diego (CA).
Normal urothelium demonstrated robust ASS1 expression throughout its full thickness. Researchers found this using immunohistochemistry on tissue specimens taken from 252 patients who had undergone surgery for muscle-invasive bladder cancer over a 20-year period.
Significant reductions in ASSI expressions were seen in majority of samples with urothelial carcinoma, small cell carcinoma, and squamous cell carcinoma.
"This finding suggests that these three major subtypes of bladder cancer, which account for more than 90% of all bladder cancers, may potentially respond to arginine-degrading therapy such as ADI-PEG 20," noted Dr. Hansel.
The researchers found that in comparison to bladder cancer patients with high ASS1 expression, the survival was significantly lower in patients having tumors with low ASS1 expression.
The researchers tested the effects of therapy with ADI-PEG 20, on cells that were deficient in ASS1 and in cells that expressed ASS1. They found that ADI-PEG 20 decreased colony formation and reduced cell viability only in cells deficient in ASS1 but had little or no effect on other cells.
In vivo testing, mice were injected with ASS1-deficient cells into subcutaneous tissue in the left flank and ASS1-expressor cells into the right flank, to test the effects of ADI-PEG 20 . The result showed that ADI-PEG 20 arrested tumor growth only in tissue containing ASS1-deficient cells.
The effect of ADI-PEG 20 is currently being evaluated in a Phase III trial for hepatocellular carcinoma and is being assessed for other cancers including melanoma and mesothelioma.
"Our results suggest that arginine deprivation may be a useful strategy for treating bladder cancer and show that ADI-PEG 20 functions through a novel signaling mechanism that includes the pathway mediated by the general control nonderepressible 2 kinase that controls autophagy and apoptosis," commented Dr. Hansel.
The study is published in The American Journal of Pathology
- Donna Hansel et al. Argininosuccinate Synthetase 1 Loss in Invasive Bladder Cancer Regulates Survival through General Control Nonderepressible 2 Kinase-Mediated Eukaryotic Initiation Factor 2α Activity and Is Targetable by Pegylated Arginine Deiminase. The American Journal of Pathology; (2017) DOI: http://dx.doi.org/10.1016/j.ajpath.2016.09.004.