Abstract 4703: Lack of expression of argininosuccinate synthetase in human cancer tissue: A biomarker for sensitivity to arginine depletion with pegylated arginine deiminase

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-04, Vol.70 (8_Supplement), p.4703-4703
• Main Authors: He, Wei, Chen, Jianhe, Zheng, Yuhui, Dai, Zaoming, He, Yan, Prestayko, Archie, Thomson, James, Wu, Bor-Wen, Bomalaski, John
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM10-4703

There is increasing awareness of metabolic abnormalities in cancer that can be exploited with new forms of treatment. In addition, there is a need for biomarkers that would help select such tumors for targeted therapies. One such metabolic abnormality is the requirement of arginine for growth by certain cancers. These cancers lack expression of argininosuccinate synthetase (ASS), the rate limiting step in the metabolism of citrulline to arginine in the Krebs urea cycle, and must obtain arginine from the circulation. It has previously been shown that hepatocellular carcinoma and metastatic melanoma have a high frequency of lack of expression of ASS. As a result, these cancers are susceptible to arginine deprivation with pegylated arginine deiminase (ADI-PEG 20) both in pre-clinical models and in phase 2 clinical trials. Similar lack of ASS expression in human tissue samples and sensitivity to arginine depletion with ADI-PEG 20 in pre-clinical models have been found in a high percentage of pancreatic, prostate, and platinum-resistant ovarian cancers. In order to explore potential other cancers that may lack ASS expression we have examined breast, lung and gastric cancer microarray samples for ASS expression by immunohistochemistry. Our results indicated that 46/111 (41.4%) breast carcinoma, 28/90 (31.1%) lung carcinoma and 68/121 (56.2%) gastric cancer were ASS negative. To explore this further, a panel of 40 ATCC tumor cell lines representing 12 different human cancer types were screened for ADI-PEG 20 induced growth inhibition using the MTS assay. Significant inhibition of proliferation in a dose dependent manner after 48 hours of ADI-PEG 20 treatment was found in 19 out of 40 tumor cell lines screened, including breast, lung, gastric, sarcoma, ovarian, prostate and pancreatic carcinomas and chronic myelogenous leukemia. Lack of ASS expression in those responding cell lines were confirmed by Western blot. These findings suggest that ASS may serve as a biomarker for targeted therapy with ADI-PEG 20. Since a high percentage of patients with breast, lung or gastric cancer lack expression of ASS, these tumors may be sensitive to arginine depletion therapy. Clinical trials of ADI-PEG 20 in these cancers are being planned. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract