Novel anticancer drug combinations exploiting arginine depletion with ADI-PEG 20 in the treatment of ASS1-negative malignant mesothelioma


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Barbara Delage1, Claude Chelala1, Dean Fennell2, Nick Lemoine1, Peter Szlosarek1

1Institute of Cancer, Barts and The London, London, UK, 2Centre for Cancer Research and Cell Biology, Belfast, UK

Abstract

Background

The asbestos-related cancer, malignant pleural mesothelioma (MPM), is a devastating disease with a median survival from diagnosis of 9-12 months. Deaths from MPM, currently 2000 per annum in the UK, are projected to increase by 25% in the next 5 years. We have shown that MPM cell lines are highly sensitive to arginine depletion, due to a deficiency of the rate-limiting enzyme in arginine synthesis, argininosuccinate synthetase (ASS). A national multicentre randomised phase II clinical trial of ADI-PEG 20, an arginine catabolizing enzyme that converts arginine into citrulline and ammonia, is planned to commence later this year. Here, we have compared the effect of ADI-PEG 20-induced arginine deprivation in ASS negative and ASS positive MPM cell lines, and explored novel drug combinations integrating ADI-PEG 20 in the treatment of MPM.

Method and Results

Initially, we confirmed that arginine deprivation has a role in 40-60% of patients with MPM, revealing that the ASS-negative phenotype is associated with a worse survival. Treatment of three ASS negative cell lines with either ADI-PEG 20 or platinum led to cell death in a dose-dependent manner, with the combination being synergistic. Next, apoptosis induction of ADI-treated ASS-negative MPM cell lines was measured by western-blot after mitochondrial/cytosolic fractionation. Novel interacting drug pathways were assessed using an ADI-treated ASS negative and its stably transfected ASS-expressing MPM cell line (control) followed by global gene expression using the Affymetrix human genome U133 Plus 2.0 Array chip combined with bioinformatic analysis.

Conclusion

The antitumour effect of ADI-PEG 20 was markedly potentiated using platinum suggesting that combining arginine depletion with the current standard of care may offer an improvement over doublet chemotherapy alone. Further work on drug combinations in ASS-negative MPM may lead to better disease control in a difficult to treat and increasingly important disease in the UK.