Abstract 4519: Small cell lung cancers lack expression of argininosuccinate synthase (ASS) and are sensitive to arginine deprivation using arginine deiminase-PEG20 (ADI-PEG20)

Abstract

Abstract Various tumor types have been shown to lack expression of the enzyme argininosuccinate synthase (ASS) that is required for the synthesis of arginine and thus rely on exogenous sources for protein synthesis requirements. These tumors may be sensitive to arginine deprivation, and the absence of ASS expression may serve as a biomarker for this sensitivity. Arginine deiminase (ADI) is a microbial enzyme that has been shown to efficiently lower peripheral blood arginine. Its therapeutic efficacy has been previously explored in the treatment of melanoma and hepatocellular cancer in early phase clinical trials but clinical efficacy in these tumor types has been limited. However, other tumor types lacking ASS may be more sensitive to arginine depletion. We have investigated ASS expression in human small cell lung cancer (SCLC) tumor tissue by immunohistochemistry (IHC) and have so far found that about 43% (7/16) of SCLC tumors were negative for ASS. SCLC has a robust initial response to chemotherapy but the majority of cases relapse and there remain limited options in the treatment of refractory disease. Based on the IHC findings and the need for novel therapies in recurrent SCLC, we explored the effects of pegylated ADI (ADI-PEG20) mediated arginine deprivation in SCLC in vitro and in vivo. We screened a panel of 10 human SCLC cell lines for ASS mRNA and protein expression by Real Time PCR and Western blot analysis. Little or no ASS was observed in 50% (5 of 10) of the SCLC cell lines examined and this frequency is approximately equivalent to that found in the SCLC tumor tissues. In cell proliferation assays a clear correlation between expression of ASS and sensitivity to ADI-PEG20 was detected. Biochemical analysis of the mechanism of ADI-PEG20 induced cell death in ADI sensitive cell lines revealed induction of autophagy and cell death through caspase independent mechanisms. Assessment of ADI-PEG20 activity in vivo using mice bearing SCLC xenografts demonstrated that ADI-PEG20 treatment of ASS negative SCLC xenografts caused significant and dose dependent inhibition of tumor growth, while no effect was observed with placebo controls. These results suggest a role for ADI-PEG20 in the treatment of SCLC, and a clinical trial exploring this treatment in patients with ASS negative SCLC by IHC has been initiated. 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 4519.