Abstract 4067: Pegylated arginine deiminase (ADI-PEG20) as a potential novel therapy for argininosuccinate synthetase-deficient acute myeloid leukemia

Abstract

Abstract Acute myeloid leukemia (AML) is the most common leukemia in adults and the second most common leukemia in children, accounting for a significant share of health care costs with ten thousand cases diagnosed per annum in the US alone. Enzyme-based therapy in the form of asparaginase has revolutionized the treatment of acute lymphoblastic leukemia and there is increasing interest in exploiting analogous tractable metabolic defects in AML. Interestingly, arginine auxotrophic tumors due to deficiency of the rate-limiting enzyme for arginine production, argininosuccinate synthetase (ASS1) are susceptible to arginine-degrading enzymes. Here, we studied whether ASS1 negativity would predict for the efficacy of pegylated arginine deiminase (ADI-PEG20) using AML cell lines and primary AML samples. A lack of ASS1 protein was identified in three of seven leukemic cell lines (K562, Kasumi and KG-1) and in all nine samples from patients with cytogenetically normal and abnormal karotype AML. Methylation of the ASS1 promoter correlated with reduced levels of ASS1 mRNA and absence of ASS1 expression. Bone marrow trephines from patients with AML revealed absence of ASS1 protein in 87% (46/53) of samples by immunohistochemistry, indicating that ASS1 expression may be a biomarker of response to ADI-PEG20 in vivo. Increased levels of ASS1 mRNA and detectable ASS1 protein expression were noted in acute promyelocytic leukemia with the translocation t(15;17). Significantly, ADI-PEG20 reduced the viability of ASS1-negative AML lines whereas the ASS1-positive control lines, Fujioka and U937, were resistant to drug-induced arginine deprivation. Recently, we have identified primary ASS1-negative AML samples with good engraftment in NOD/SCID mice and are proceeding to test the efficacy of ADI-PEG20 using this primary AML xenograft model. Based on our preliminary data and the potential efficacy with low toxicity of arginine deprivation in humans, a phase II trial of ADI-PEG20 is planned in patients with relapsed AML. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4067. doi:10.1158/1538-7445.AM2011-4067