Scientists from academic institutions reported at the 2013 annual American Association for Cancer Research meeting, results from preclinical studies which showed that certain bladder cancers and mesotheliomas have metabolic changes and are more likely to respond to treatment with ADI-PEG 20 (pegylated arginine deiminase) if they are deficient in the enzyme, argininosuccinate synthetase (ASS). This enzyme plays an important role in the synthesis of the amino acid arginine required for proteins in cell growth and function. Its deficiency in certain cancer cells requires these cells to obtain arginine from the circulation in order to survive. ADI-PEG 20 destroys arginine in circulation thereby preventing the cancers from growing.
Gupta et al from The Cleveland Clinic (abstract No. 11) reported on the identification of ASS deficient bladder cancers, and found that 110/187 (58.5%) had marked reductions in levels of ASS. Tissue culture studies with an ASS deficient bladder cancer cell line showed that ADI-PEG 20 treatment resulted in activation of a kinase (GCN2) known to be triggered by amino acid deprivation. Downstream changes also included induction of a gene (CHOP) that correlated with a reduction in cell viability. These findings demonstrate that ADI-PEG 20 regulates gene expression and changes in cellular metabolism, and suggest that bladder cancers may be good candidates for ADI-PEG 20 therapy.