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

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.

• Authors: Kathryn Evans, JianXin Duan, Tara Pritchard, Connor D Jones, Lisa McDermott, Zhaohui Gu, Cara E Toscan, Narimanne El-Zein, Chelsea Mayoh, Stephen W Erickson, Yuelong Guo, Fanying Meng, Donald Jung, Komal S Rathi, Kathryn G Roberts, Charles G Mullighan, Chi-Sheng Shia, Tillman Pearce, Beverly A Teicher, Malcolm A Smith, Richard B Lock
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 25 Issue 14 Pg. 4493-4503 (07 15 2019) ISSN: 1557-3265 [Electronic] United States
• PMID: 31015346 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents, Alkylating
• Prodrugs
• AKR1C3 protein, human
• Aldo-Keto Reductase Family 1 Member C3

Topics

• Aldo-Keto Reductase Family 1 Member C3 (metabolism)
• Animals
• Antineoplastic Agents, Alkylating (pharmacology)
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival
• Drug Evaluation, Preclinical
• Female
• Humans
• Macaca fascicularis
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, metabolism)
• Prodrugs (pharmacology)
• Treatment Outcome
• Xenograft Model Antitumor Assays