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https://hdl.handle.net/2440/121841
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Type: | Journal article |
Title: | OBI-3424, a novel AKR1c3-activated prodrug, exhibits potent efficacy against preclinical models of T-ALL |
Author: | Evans, K. Duan, J.X. Pritchard, T. Jones, C.D. McDermott, L. Gu, Z. Toscan, C.E. El-Zein, N. Mayoh, C. Erickson, S.W. Guo, Y. Meng, F. Jung, D. Rathi, K.S. Roberts, K.G. Mullighan, C.G. Shia, C.S. Pearce, T. Teicher, B.A. Smith, M.A. et al. |
Citation: | Clinical Cancer Research, 2019; 25(14):4493-4503 |
Publisher: | American Association for Cancer Research |
Issue Date: | 2019 |
ISSN: | 1078-0432 1557-3265 |
Statement of Responsibility: | Kathryn Evans, JianXin Duan, Tara Pritchard, Connor D. Jones, Lisa McDermott ... Charles G. Mullighan ... et al. |
Abstract: | 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. |
Keywords: | Cell Line, Tumor Animals Mice, Inbred NOD Macaca fascicularis Humans Mice Mice, SCID Antineoplastic Agents, Alkylating Prodrugs Treatment Outcome Drug Evaluation, Preclinical Xenograft Model Antitumor Assays Cell Proliferation Cell Survival Female Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Aldo-Keto Reductase Family 1 Member C3 |
Rights: | © 2019, American Association for Cancer Research |
DOI: | 10.1158/1078-0432.CCR-19-0551 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1059804 http://purl.org/au-research/grants/nhmrc/1157871 |
Published version: | http://dx.doi.org/10.1158/1078-0432.ccr-19-0551 |
Appears in Collections: | Aurora harvest 8 Medicine publications |
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