ABSTRACT
Inhibition of the Menin (MEN1) and MLL (MLL1, KMT2A) interaction is a potential therapeutic strategy for MLL-rearranged (MLL-r) leukemia. Structure-based design yielded the potent, highly selective, and orally bioavailable small-molecule inhibitor VTP50469. Cell lines carrying MLL rearrangements were selectively responsive to VTP50469. VTP50469 displaced Menin from protein complexes and inhibited chromatin occupancy of MLL at select genes. Loss of MLL binding led to changes in gene expression, differentiation, and apoptosis. Patient-derived xenograft (PDX) models derived from patients with either MLL-r acute myeloid leukemia or MLL-r acute lymphoblastic leukemia (ALL) showed dramatic reductions of leukemia burden when treated with VTP50469. Multiple mice engrafted with MLL-r ALL remained disease free for more than 1 year after treatment. These data support rapid translation of this approach to clinical trials.
Subject(s)
Chromatin/drug effects , Gene Expression Regulation, Leukemic/drug effects , Leukemia, Myeloid, Acute/drug therapy , Proto-Oncogene Proteins/drug effects , Animals , Apoptosis/drug effects , Apoptosis/genetics , Cell Differentiation/drug effects , Cell Differentiation/genetics , Cell Proliferation/drug effects , Cell Proliferation/genetics , Chromatin/genetics , Gene Expression Regulation, Leukemic/genetics , Gene Rearrangement/drug effects , Gene Rearrangement/genetics , Humans , Leukemia, Myeloid, Acute/genetics , Mice , Proto-Oncogene Proteins/genetics , Transcription Factors/drug effects , Transcription Factors/geneticsABSTRACT
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 nonhuman primates, and assessed the in vivo efficacy of OBI-3424 against a large panel of patient-derived xenografts (PDX). RESULTS: AKR1C3 mRNA expression was significantly higher in primary T-lineage ALL (T-ALL; n = 264) than B-lineage ALL (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 nine of nine ALL PDXs by 17.1-77.8 days (treated/control values 2.5-14.0), and disease regression was observed in eight of nine PDXs. A significant reduction (P < 0.0001) in bone marrow infiltration at day 28 was observed in four of six 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 two 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.
