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.
Ghazaly et al from Barts Cancer Institute, Queen Mary University of London (abstract No. 1885) determined the metabolic changes induced by ADI-PEG 20 treatment in a panel of bladder cancer and mesothelioma cell lines. Arginine depletion was noted in all treated cell lines irrespective of ASS expression, however the reduction was at least one-log-fold greater in the ASS-negative tumor cells. The amino acids citrulline and glutamine were upregulated specifically in ASS-negative tumor cell lines. Another impact of ADI-PEG 20 treatment was on pyrimidine metabolism in the ASS-deficient tumor cells with up-regulation of thymine and down-regulation of thymidine. Notably, the reduction of the thymidine nucleotide pool was linked to suppression of thymidylate synthetase and dihydrofolate reductase, important enzymes in the folate pathways. This study provides an insight into possible metabolic pathways affected by ADI-PEG 20. The impact of ADI-PEG 20 on thymidine metabolism, in particular, may possibly be employed as a potential biomarker for optimizing the efficacy of ADI-PEG 20 in the treatment of arginine auxotrophic cancers.
"These data provide further information on the metabolic changes induced in cancer cells by ADI-PEG 20, and suggests that arginine deprivation therapy with ADI-PEG 20 may have utility in a variety of tumor types. Polaris is currently sponsoring a worldwide phase 3 pivotal clinical trial with single agent ADI-PEG 20 in hepatocellular carcinoma," said John Bomalaski , M.D., Executive Vice President, Medical Affairs, of Polaris. "We also have a number of phase 1 and phase 2 clinical trials underway with ADI-PEG 20 including mesothelioma, melanoma and prostate cancer. Our study in prostate cancer is the first to combine ADI-PEG 20 with another anticancer agent, docetaxel and we are excited with the initial results and the potential for future combination cancer therapy with ADI-PEG 20. In addition, another study combines ADI-PEG 20 with cisplatin, an agent with extensive use in a variety of cancers," he added.