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Abstract 2745: AKR1C3 is a potential biomarker of T-cell acute lymphoblastic leukemia sensitivity to the pre-prodrug PR-104.

Despite the success of current therapies for childhood acute lymphoblastic leukemia (ALL), novel treatments are required to treat high-risk or relapsed patients. PR-104 is a pre-prodrug hydrolyzed in vivo to PR-104A, which is then metabolized under hypoxia by one-electron reductases to DNA cross-linking metabolites. PR-104A is also activated under aerobic conditions by aldo-keto reductase 1C3 (AKR1C3). We previously showed profound in vivo efficacy of PR-104 (550 mg/kg IP weekly x 6) against a panel of T- and B-ALL xenografts derived from direct patient explants in immune-deficient mice. However, testing at doses as low as 10% of the MTD (50-200 mg/kg) showed retention of efficacy against a T-ALL but not a B-ALL xenograft. This study aimed to further evaluate PR-104 as a novel treatment for high-risk T-ALL by testing its in vivo efficacy against a large panel of pediatric ALL xenografts both as a single agent and in combination with established drugs. We also aimed to evaluate AKR1C3 as a biomarker of in vivo PR-104 sensitivity in T-ALL. PR-104A was significantly more cytotoxic in vitro against 8 T-ALL compared to 8 B-ALL xenografts (median IC 50 value 9-fold higher in B-ALL; P Citation Format: Donya Moradi Manesh, Hernan Carol, Kathryn Evans, Jennifer Richmond, Stephen Jamieson, William R. Wilson, Peter J. Houghton, Malcolm A. Smith, Richard B. Lock. AKR1C3 is a potential biomarker of T-cell acute lymphoblastic leukemia sensitivity to the pre-prodrug PR-104. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2745. doi:10.1158/1538-7445.AM2013-2745