Children's Cancer Institute, School of Women's and Children's Health, UNSW Sydney, Sydney, Australia.
Ascentawits Pharmaceuticals, Ltd, Nanshan Shenzhen, China.
Clin Cancer Res. 2019 Jul 15;25(14):4493-4503. doi: 10.1158/1078-0432.CCR-19-0551. Epub 2019 Apr 23.
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).
We assessed AKR1C3 expression by RNA-Seq and immunoblotting, and evaluated the cytotoxicity of OBI-3424. We investigated the pharmacokinetics of OBI-3424 in mice and nonhuman primates, and assessed the efficacy of OBI-3424 against a large panel of patient-derived xenografts (PDX).
AKR1C3 mRNA expression was significantly higher in primary T-lineage ALL (T-ALL; = 264) than B-lineage ALL (B-ALL; = 1,740; < 0.0001), and OBI-3424 exerted potent cytotoxicity against T-ALL cell lines and PDXs. , 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 ( < 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 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.
OBI-3424 exerted profound 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.
OBI-3424 是一种高度选择性的前药，可被醛酮还原酶家族 1 成员 C3（AKR1C3）转化为有效的 DNA 烷化剂。OBI-3424 已进入肝细胞癌和去势抵抗性前列腺癌的临床测试，它代表了急性淋巴细胞白血病（ALL）的一种潜在的新型治疗方法。
我们通过 RNA-Seq 和免疫印迹评估 AKR1C3 的表达，并评估 OBI-3424 的细胞毒性。我们研究了 OBI-3424 在小鼠和非人类灵长类动物中的药代动力学，并评估了 OBI-3424 对大型患者来源异种移植（PDX）面板的疗效。
原发性 T 系急性淋巴细胞白血病（T-ALL；n=264）中 AKR1C3 mRNA 表达明显高于 B 系急性淋巴细胞白血病（B-ALL；n=1740；<0.0001），并且 OBI-3424 对 T-ALL 细胞系和 PDX 具有强大的细胞毒性。在 9 个 ALL PDX 中，OBI-3424 显著延长了 9 个事件无进展生存期（EFS），延长了 17.1-77.8 天（治疗/对照值为 2.5-14.0），并且观察到 8 个 PDX 疾病消退。在 6 个可评估的 T-ALL PDX 中有 4 个在第 28 天观察到骨髓浸润显著减少（<0.0001）。使用已通过慢病毒转导稳定过表达 AKR1C3 的 B-ALL PDX 验证了 AKR1C3 在对 OBI-3424 反应中的重要性。与单独使用每种药物相比，OBI-3424 与 nelarabine 联合使用在两个 T-ALL PDX 中延长了小鼠 EFS。
OBI-3424 对主要来源于侵袭性和致命性疾病的 T-ALL PDX 具有显著疗效，因此在 AKR1C3 生物标志物驱动的临床试验中，可能代表了侵袭性和耐药性 T-ALL 的新型治疗方法。
