Ntafoulis Ioannis, Koolen Stijn L W, van Tellingen Olaf, den Hollander Chelsea W J, Sabel-Goedknegt Hendrika, Dijkhuizen Stephanie, Haeck Joost, Reuvers Thom G A, de Bruijn Peter, van den Bosch Thierry P P, van Dis Vera, Gao Zhenyu, Dirven Clemens M F, Leenstra Sieger, Lamfers Martine L M
Department of Neurosurgery, Brain Tumor Center, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands.
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands.
Pharmaceuticals (Basel). 2024 Dec 14;17(12):1687. doi: 10.3390/ph17121687.
Glioblastoma is an aggressive and incurable type of brain cancer. Little progress has been made in the development of effective new therapies in the past decades. The blood-brain barrier (BBB) and drug efflux pumps, which together hamper drug delivery to these tumors, play a pivotal role in the gap between promising preclinical findings and failure in clinical trials. Therefore, selecting drugs that can reach the tumor region in pharmacologically effective concentrations is of major importance.
In the current study, we utilized a drug selection platform to identify candidate drugs by combining in vitro oncological drug screening data and pharmacokinetic (PK) profiles for central nervous system (CNS) penetration using the multiparameter optimization (MPO) score. Furthermore, we developed intracranial patient-derived xenograft (PDX) models that recapitulated the in situ characteristics of glioblastoma and characterized them in terms of vascular integrity, BBB permeability and expression of ATP-binding cassette (ABC) transporters. Omacetaxine mepesuccinate (OMA) was selected as a proof-of-concept drug candidate to validate our drug selection pipeline.
We assessed OMA's PK profile in three different orthotopic mouse PDX models and found that OMA reaches the brain tumor tissue at concentrations ranging from 2- to 11-fold higher than in vitro IC values on patient-derived glioblastoma cell cultures.
This study demonstrates that OMA, a drug selected for its in vitro anti-glioma activity and CNS- MPO score, achieves brain tumor tissue concentrations exceeding its in vitro IC values in patient-derived glioblastoma cell cultures, as shown in three orthotopic mouse PDX models. We emphasize the importance of such approaches at the preclinical level, highlighting both their significance and limitations in identifying compounds with potential clinical implementation in glioblastoma.
胶质母细胞瘤是一种侵袭性且无法治愈的脑癌类型。在过去几十年中，有效的新疗法开发进展甚微。血脑屏障（BBB）和药物外排泵共同阻碍药物向这些肿瘤的递送，在有前景的临床前研究结果与临床试验失败之间的差距中起关键作用。因此，选择能够以药理有效浓度到达肿瘤区域的药物至关重要。
在本研究中，我们利用一个药物筛选平台，通过结合体外肿瘤药物筛选数据和使用多参数优化（MPO）评分的中枢神经系统（CNS）渗透药代动力学（PK）概况来识别候选药物。此外，我们建立了颅内患者来源异种移植（PDX）模型，该模型概括了胶质母细胞瘤的原位特征，并在血管完整性、血脑屏障通透性和ATP结合盒（ABC）转运蛋白表达方面对其进行了表征。选择高三尖杉酯碱甲磺酸盐（OMA）作为概念验证药物候选物，以验证我们的药物筛选流程。
我们在三种不同的原位小鼠PDX模型中评估了OMA的PK概况，发现OMA在脑肿瘤组织中达到的浓度比患者来源的胶质母细胞瘤细胞培养物中的体外IC值高2至11倍。
本研究表明，OMA作为一种因其体外抗胶质瘤活性和中枢神经系统MPO评分而被选择的药物，在三种原位小鼠PDX模型中显示，其在脑肿瘤组织中的浓度超过了患者来源的胶质母细胞瘤细胞培养物中的体外IC值。我们强调了此类方法在临床前水平的重要性，突出了它们在识别具有胶质母细胞瘤潜在临床应用价值的化合物方面的意义和局限性。
