OBI-3424, a novel AKR1C3-activated prodrug, exhibits potent efficacy against preclinical models of T-ALL

Purpose: OBI-3424 is a highly selective prodrug that is converted by aldo-keto reductase family 1 member C3 (AKR1C3) to a potent DNA alkylating agent. OBI-3424 has entered clinical testing for hepatocellular carcinoma and castrate resistant prostate cancer, and it represents a potentially novel treatment for acute lymphoblastic leukemia (ALL). Experimental Design: We assessed AKR1C3 expression by RNA-Seq and immunoblotting, and evaluated the in vitro cytotoxicity of OBI-3424. We investigated the pharmacokinetics of OBI-3424 in mice and non-human primates, and assessed the in vivo efficacy of OBI-3424 against a large panel of patient-derived xenografts (PDXs). Results: AKR1C3 mRNA expression was significantly higher in primary T-ALL (n=264) than B-ALL (n=1,740) (P<0.0001) and OBI-3424 exerted potent cytotoxicity against T-ALL cell lines and PDXs. In vivo, OBI-3424 significantly prolonged the event-free survival (EFS) of 9/9 ALL PDXs by 17.1-77.8 days (Treated/Control values 2.5-14.0), and disease regression was observed in 8/9 PDXs. A significant reduction (P<0.0001) in bone marrow infiltration at Day 28 was observed in 4/6 evaluable T-ALL PDXs. The importance of AKR1C3 in the in vivo response to OBI-3424 was verified using a B-ALL PDX that had been lentivirally transduced to stably overexpress AKR1C3. OBI-3424 combined with nelarabine resulted in prolongation of mouse EFS compared with each single agent alone in 2 T-ALL PDXs. Conclusions: OBI-3424 exerted profound in vivo efficacy against T-ALL PDXs derived predominantly from aggressive and fatal disease, and therefore may represent a novel treatment for aggressive and chemoresistant T-ALL in an AKR1C3 biomarker-driven clinical trial.