2. Academic Validation
  3. OBI-3424, a Novel AKR1C3-Activated Prodrug, Exhibits Potent Efficacy against Preclinical Models of T-ALL

OBI-3424, a Novel AKR1C3-Activated Prodrug, Exhibits Potent Efficacy against Preclinical Models of T-ALL

  • Clin Cancer Res. 2019 Jul 15;25(14):4493-4503. doi: 10.1158/1078-0432.CCR-19-0551.
Kathryn Evans 1,  JianXin Duan 2,  Tara Pritchard 1,  Connor D Jones 1,  Lisa McDermott 1,  Zhaohui Gu 3,  Cara E Toscan 1,  Narimanne El-Zein 1,  Chelsea Mayoh 1,  Stephen W Erickson 4,  Yuelong Guo 4,  Fanying Meng 2,  Donald Jung 2,  Komal S Rathi 5,  Kathryn G Roberts 3,  Charles G Mullighan 3,  Chi-Sheng Shia 6,  Tillman Pearce 6,  Beverly A Teicher 7,  Malcolm A Smith 7,  Richard B Lock 8
Affiliations

Affiliations

  • 1 Children's Cancer Institute, School of Women's and Children's Health, UNSW Sydney, Sydney, Australia.
  • 2 Ascentawits Pharmaceuticals, Ltd, Nanshan Shenzhen, China.
  • 3 Department of Pathology and the Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • 4 RTI International, Research Triangle Park, North Carolina.
  • 5 Division of Oncology and Center for Childhood Cancer Research, Department of Biomedical and Health Informatics and Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
  • 6 OBI Pharma, Inc. Taipei, Taiwan.
  • 7 NCI, Bethesda, Maryland.
  • 8 Children's Cancer Institute, School of Women's and Children's Health, UNSW Sydney, Sydney, Australia. [email protected].
PMID: 31015346 DOI: 10.1158/1078-0432.CCR-19-0551
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.

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