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https://hdl.handle.net/2440/121841
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dc.contributor.author | Evans, K. | - |
dc.contributor.author | Duan, J.X. | - |
dc.contributor.author | Pritchard, T. | - |
dc.contributor.author | Jones, C.D. | - |
dc.contributor.author | McDermott, L. | - |
dc.contributor.author | Gu, Z. | - |
dc.contributor.author | Toscan, C.E. | - |
dc.contributor.author | El-Zein, N. | - |
dc.contributor.author | Mayoh, C. | - |
dc.contributor.author | Erickson, S.W. | - |
dc.contributor.author | Guo, Y. | - |
dc.contributor.author | Meng, F. | - |
dc.contributor.author | Jung, D. | - |
dc.contributor.author | Rathi, K.S. | - |
dc.contributor.author | Roberts, K.G. | - |
dc.contributor.author | Mullighan, C.G. | - |
dc.contributor.author | Shia, C.S. | - |
dc.contributor.author | Pearce, T. | - |
dc.contributor.author | Teicher, B.A. | - |
dc.contributor.author | Smith, M.A. | - |
dc.contributor.author | et al. | - |
dc.date.issued | 2019 | - |
dc.identifier.citation | Clinical Cancer Research, 2019; 25(14):4493-4503 | - |
dc.identifier.issn | 1078-0432 | - |
dc.identifier.issn | 1557-3265 | - |
dc.identifier.uri | http://hdl.handle.net/2440/121841 | - |
dc.description.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. | - |
dc.description.statementofresponsibility | Kathryn Evans, JianXin Duan, Tara Pritchard, Connor D. Jones, Lisa McDermott ... Charles G. Mullighan ... et al. | - |
dc.language.iso | en | - |
dc.publisher | American Association for Cancer Research | - |
dc.rights | © 2019, American Association for Cancer Research | - |
dc.source.uri | http://dx.doi.org/10.1158/1078-0432.ccr-19-0551 | - |
dc.subject | Cell Line, Tumor | - |
dc.subject | Animals | - |
dc.subject | Mice, Inbred NOD | - |
dc.subject | Macaca fascicularis | - |
dc.subject | Humans | - |
dc.subject | Mice | - |
dc.subject | Mice, SCID | - |
dc.subject | Antineoplastic Agents, Alkylating | - |
dc.subject | Prodrugs | - |
dc.subject | Treatment Outcome | - |
dc.subject | Drug Evaluation, Preclinical | - |
dc.subject | Xenograft Model Antitumor Assays | - |
dc.subject | Cell Proliferation | - |
dc.subject | Cell Survival | - |
dc.subject | Female | - |
dc.subject | Precursor T-Cell Lymphoblastic Leukemia-Lymphoma | - |
dc.subject | Aldo-Keto Reductase Family 1 Member C3 | - |
dc.title | OBI-3424, a novel AKR1c3-activated prodrug, exhibits potent efficacy against preclinical models of T-ALL | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1158/1078-0432.CCR-19-0551 | - |
dc.relation.grant | http://purl.org/au-research/grants/nhmrc/1059804 | - |
dc.relation.grant | http://purl.org/au-research/grants/nhmrc/1157871 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Mullighan, C.G. [0000-0002-1871-1850] | - |
Appears in Collections: | Aurora harvest 8 Medicine publications |
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