Abstract 2745: AKR1C3 is a potential biomarker of T-cell acute lymphoblastic leukemia sensitivity to the pre-prodrug PR-104.
Authors: Moradi Manesh Donya , Carol Hernan , Evans Kathryn , Richmond Jennifer , Jamieson Stephen , Wilson William R. , Houghton Peter J. , Smith Malcolm A. , Lock Richard B. 
Published: August 2014

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 IC50 value 9-fold higher in B-ALL; P&lt;0.0001), indicating that the difference in sensitivity is a cell-intrinsic phenomenon. Microarray analysis of gene expression, qRT-PCR and immunoblotting showed that AKR1C3 expression was significantly higher in T-ALL compared with B-ALL xenografts (P&lt;0.01). We also observed a strong correlation between AKR1C3 mRNA and protein expression and enzymatic activity (P&lt;0.0001). Moreover, AKR1C3 protein expression significantly correlated with in vitro sensitivity of xenografts to PR104A as assessed by Alamar blue cytotoxicity assay (P=0.0003). The in vivo efficacy of PR-104 was assessed using stringent objective response criteria modeled after the clinical setting, as well as time to event measurements. PR-104 administered as a single agent at a dose that provides pharmacokinetics that are readily achievable in adult leukemia patients (200 mg/kg weekly x 2) was more effective in inducing regression and progression delay of 3/3 chemoresistant T-ALL xenografts compared with an induction-type regimen of vincristine (0.15 mg/kg weekly x 2), dexamethasone (5 mg/kg daily x 5 x 2) and L-asparaginase (1,000 KU/kg daily x 5 x 2) (VXL). However, no therapeutic enhancement was observed in the combination of PR-104 with VXL. These results indicate that PR-104 shows promise as a novel therapy for the treatment of aggressive and chemoresistant T-ALL, and that AKR1C3 is a potential biomarker of in vivo PR-104 efficacy. The optimal combinations of PR-104 that result in therapeutic synergy with established drugs remain to be defined. Our findings have implications for the clinical development of PR-104, since patients with T-ALL may represent a particularly responsive population. This study was supported by NCI NO1CM42216 and Proacta, Inc.

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