Yang Bing-Heng, Lin Wei-Zhi, Chiang Yu-Ting, Chen Yeu-Chin, Chung Chi-Hsiang, Chien Wu-Chien, Shiau Chia-Yang
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
Division of Clinical Pathology, Department of Pathology, Tri-Service General Hospital, Taipei, Taiwan.
Front Oncol. 2022 Feb 2;12:809014. doi: 10.3389/fonc.2022.809014. eCollection 2022.
Although several epigenetic drugs have been reported to have therapeutic efficacy for some hematologic neoplasms (HNs) in clinical trials, few achieved disease-free survival benefit. The traditional drug discovery pathway is costly and time-consuming, and thus, more effective strategies are required. We attempted to facilitate epigenetic drug repositioning for therapy of HNs by screening the Human Epigenetic Drug Database (HEDD) in the web, conducting a bench-work cytotoxicity test and a retrospective nationwide cohort study prior to a clinical trial.
Four FDA-approved epigenetic drugs with antitumor properties and completion of clinical phase II trials were selected from HEDD. Hydralazine (HDZ) and valproate (VAL) among the four were selected with higher cytotoxicity to HN cells, no matter whether carrying the mutation or not. Both of them were chosen for a cohort study using the Longitudinal Health Insurance Database (LHID) 2000-2015 (N = 1,936,512), a subset of the National Health Insurance Research Database (NHIRD, N= 25.68 millions) in Taiwan.
In the initial cohort, HDZ or VAL exposure subjects (11,049) and matching reference subjects (44,196) were enrolled according to maximal daily consumption (300/2,100 mg per day of HDZ/VAL). The HN incidence in HDZ and VAL exposure groups reduced from 4.97% to 3.90% ( <.001) and 4.45% ( = .075), respectively. A further cohort study on HDZ at a lower range of the WHO defined daily dose (<34 mg per day) and HN incidence of HDZ exposure subjects (75,612) reduced from 5.01% to 4.16% ( = 1.725 × 10 ) compared to the reference subjects (302,448).
An association of a chronically prescribed HDZ, even prescribed low dose, with reduction of overall incidence rate and in most subgroups of HN was observed in our study. Repositioning HDZ for HN management may be feasible. This is the first nationwide cohort study of the epigenetics-associated risk evaluation of overall HN in the existing literature, showing an effective method with a wider scope to inform contemporary clinical trials of epigenetic drugs in the future.
尽管在临床试验中已有几种表观遗传药物被报道对某些血液系统肿瘤（HNs）具有治疗效果，但很少能实现无病生存获益。传统的药物研发途径成本高且耗时，因此需要更有效的策略。我们试图通过在网上筛选人类表观遗传药物数据库（HEDD）、进行基础细胞毒性试验以及在临床试验前开展一项全国性回顾性队列研究，来促进表观遗传药物重新定位用于治疗血液系统肿瘤。
从HEDD中选择四种已获美国食品药品监督管理局（FDA）批准且具有抗肿瘤特性并完成II期临床试验的表观遗传药物。这四种药物中的肼屈嗪（HDZ）和丙戊酸盐（VAL）对血液系统肿瘤细胞具有较高的细胞毒性，无论是否携带该突变。二者均被选入一项队列研究，该研究使用了台湾地区全民健康保险研究数据库（NHIRD，N = 2568万）的一个子集——2000 - 2015年纵向健康保险数据库（LHID）（N = 1936512）。
在初始队列中，根据最大日摄入量（HDZ/VAL分别为每日300/2100毫克）纳入HDZ或VAL暴露组受试者（11049名）和匹配的参照组受试者（44196名）。HDZ和VAL暴露组的血液系统肿瘤发病率分别从4.97%降至3.90%（P <.001）和4.45%（P =.075）。对HDZ进行的另一项队列研究，在世界卫生组织定义的较低日剂量范围（每日<34毫克）内，HDZ暴露组受试者（75612名）的血液系统肿瘤发病率与参照组受试者（302448名）相比，从5.01%降至4.16%（P = 1.725×10⁻⁴）。
在我们的研究中观察到，长期服用HDZ（即使是低剂量）与总体发病率降低以及在大多数血液系统肿瘤亚组中发病率降低之间存在关联。将HDZ重新定位用于血液系统肿瘤管理可能是可行的。这是现有文献中第一项关于血液系统肿瘤整体表观遗传学相关风险评估的全国性队列研究，展示了一种有效的方法，可为未来表观遗传药物的当代临床试验提供更广泛的信息。
