Abstract 4520: Arginine deprivation therapy in malignant peripheral nerve sheath tumor and gastrointestinal stromal tumor: potential therapeutic effects of pegylated arginine deiminase in argininosuccinate synthetase negative sarcomas

Abstract

Abstract Malignant peripheral nerve sheath tumor (MPNST) is an aggressive, high grade sarcoma which is strongly associated with neurofibromatosis 1. No effective therapy currently exists for MPNST. Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. Most GIST harbor activating mutations of KIT or platelet derived growth factor receptor-alpha (PDGFRA). First-line therapy for GIST consists of imatinib mesylate, a small molecule inhibitor which targets KIT and of PDGFRA. Significantly, approximately 50% of GIST will develop resistance to imatinib. Depriving cancer cells of amino acids has shown promise as a therapeutic strategy. Arginine is a semi-essential amino acid which can be synthesized from citrulline via a two-step process involving argininosuccinate synthetase (ASS) and argininosuccinate lyase. Loss of expression of ASS has been identified in several cancer cell lines and human cancer types. This deficiency can be targeted by adminstration of a pegylated form of arginine deiminase (ADI-PEG20), a prokaryotic enzyme which degrades arginine into its citrulline precursor. Neoplastic cells which do not produce ASS starve since they cannot recycle citrulline into arginine. Proof of principle has been shown with ADI-PEG20 in patients with hepatocellular carcinoma or metastatic melanoma. In order to explore ASS negativity in sarcoma as a potential prelude to clinical trials of ADI-PEG 20, we examined a series of formalin fixed paraffin embedded sarcomas by immunohistochemistry. A total of 45 different sarcomas were represented, and 619/701 (88%) were negative for ASS expression. In that group, for MPNST and GIST, we found 92% (6/74) and 97% (3/95) respectively, to lack expression of ASS. These results suggested that MPNST and GIST may be susceptible to arginine deprivation therapy by ADI-PEG20. Treatment of ST8814 and STS26T, two MPNST cell lines, with ADI-PEG20 resulted in a dose-dependent decrease in proliferation in 72 hour cytotoxicity assays. A concentration of 0.3 µg/mL and 0.08 µg/mL inhibited cell proliferation by ∼50% (IC50) in ST8814 and STS26T respectively. Similarly, treatment of GIST-T1 and GIST 882, two GIST cell lines, also showed a decrease in proliferation in 72 hour proliferation assays with an IC50 of 0.08 µg/mL for both cell lines. However, apoptosis was not induced by treatment with ADI-PEG20 in ST8814, STS26T, or GIST-T1. Taken together, these results show that MPNST and GIST cell lines are responsive to treatment by ADI-PEG20, and that ADI-PEG20 inhibits proliferation via a non-apoptosis dependent mechanism. These data suggest that ADI-PEG20 may show utility in the treatment of MPNST and GIST, two sarcomas for which additional therapeutic targets are needed. 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 nr 4520.