Abstract A23: Frequent ASS1 deficiency in bladder cancer and sensitivity to pegylated arginine deiminase (ADI-PEG20): A potential novel therapeutic strategy

Abstract

Abstract Tumors deficient in argininosuccinate synthetase (ASS1), a key enzyme involved in arginine synthesis, are auxtrophic for arginine and sensitive to amino acid deprivation. Based on reports of ASS1 negativity and arginine auxotrophy of prostate and renal cancers, we investigated the role of ASS1 and arginine depletion in bladder cancer, a common urological malignancy with limited treatment options for advanced disease. First, we screened 8 bladder cancer cell lines revealing very low mRNA levels and low or absent ASS1 protein in 4 of 8 cell lines. The ASS1 negative cell lines were all hypermethylated at the ASS1 promoter, compared with the ASS1 – positive cell lines, which were hypomethylated. An analysis of 48 patients with bladder cancer revealed 65% were ASS1 -negative by immunohistochemistry, with evidence for ASS1 methylation as a mechanism for ASS1 inactivation. There was no correlation between ASS1 loss and the type, grade or stage of bladder tumor. Next, we exposed two ASS1 -negative and two ASS1 -positive bladder cancer cell lines to pegylated arginine deiminase (ADI-PEG20), an arginine depleting agent that is currently undergoing evaluation in several clinical trials in patients with solid malignancies. The ASS1-negative, but not the ASS1 -positive, bladder cancer cell lines were sensitive to ADI-PEG20 treatment. Current work is focussed on determining whether there is enhanced cell killing when ADI-PEG20 is combined with cisplatin-based chemotherapy. In summary, ADI-PEG20 is a potential novel therapeutic approach in the treatment of ASS1 – negative bladder cancer and warrants further investigation in the clinic. Citation Information: Clin Cancer Res 2010;16(14 Suppl):A23.