Treatment with small-molecule inhibitors, guided by precision medicine has improved patient outcomes in multiple cancer types. However, these compounds are often not effective against central nervous system (CNS) tumors. The failure of precision medicine approaches for CNS tumors is frequently attributed to the inability of these compounds to cross the blood-brain barrier (BBB), which impedes intratumoral target engagement. This is complicated by the fact that information on CNS penetration in CNS-tumor patients is still very limited. Herein, we evaluated cerebrospinal fluid (CSF) drug penetration, a well-established surrogate for CNS-penetration, in pediatric brain tumor patients. We analyzed 7 different oral anti-cancer drugs and their metabolites by high performance liquid chromatography mass spectrometry (HPLC-MS) in 42 CSF samples obtained via Ommaya reservoirs of 9 different patients. Moreover, we related the resulting data to commonly applied predictors of BBB-penetration including ABCB1 substrate-character, physicochemical properties and in silico algorithms. First, the measured CSF drug concentrations depicted good intra- and interpatient precision. Interestingly, ribociclib, vorinostat and imatinib showed high (> 10 nM), regorafenib and dasatinib moderate (1–10 nM) penetrance. In contrast, panobinostat und nintedanib were not detected. In addition, we identified active metabolites of imatinib and ribociclib. Comparison to well-established BBB-penetrance predictors confirmed low molecular weight, high proportion of free-drug and low ABCB1-mediated efflux as central factors. However, evaluation of diverse in silico algorithms showed poor correlation within our dataset. In summary, our study proves the feasibility of measuring CSF concentration via Ommaya reservoirs thus setting the ground for utilization of this method in future clinical trials. Moreover, we demonstrate CNS presence of certain small-molecule inhibitors and even active metabolites in CSF of CNS-tumor patients and provide a potential guidance for physicochemical and biological factors favoring CNS-penetration.

中文翻译：

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儿科脑肿瘤患者靶向治疗的脑脊液渗透。

在精准医学的指导下，小分子抑制剂治疗改善了多种癌症类型的患者预后。然而，这些化合物通常不能有效对抗中枢神经系统（CNS）肿瘤。中枢神经系统肿瘤精准医疗方法的失败通常归因于这些化合物无法穿过血脑屏障（BBB），从而阻碍了肿瘤内靶点的参与。由于有关中枢神经系统肿瘤患者的中枢神经系统渗透的信息仍然非常有限，这一事实使情况变得复杂。在此，我们评估了儿科脑肿瘤患者的脑脊液 (CSF) 药物渗透，这是一种公认​​的中枢神经系统渗透替代指标。我们通过高效液相色谱质谱 (HPLC-MS) 分析了 9 名不同患者通过 Ommaya 储库获得的 42 份脑脊液样本中的 7 种不同的口服抗癌药物及其代谢物。此外，我们将所得数据与常用的 BBB 渗透预测因子相关联，包括 ABCB1 底物特征、物理化学性质和计算机算法。首先，测量的脑脊液药物浓度显示出良好的患者内和患者间精度。有趣的是，ribociclib、vorinostat 和伊马替尼显示出高外显率 (> 10 nM)，瑞戈非尼和达沙替尼显示出中等外显率 (1–10 nM)。相反，没有检测到帕比司他和尼达尼布。此外，我们还鉴定了伊马替尼和 ribociclib 的活性代谢物。与成熟的 BBB 外显率预测因子相比，证实了低分子量、高比例的游离药物和低 ABCB1 介导的外排是核心因素。然而，对各种计算机算法的评估显示我们的数据集中的相关性很差。总之，我们的研究证明了通过 Ommaya 水库测量 CSF 浓度的可行性，从而为未来临床试验中使用该方法奠定了基础。此外，我们证明中枢神经系统肿瘤患者的脑脊液中存在某些小分子抑制剂甚至活性代谢物，并为有利于中枢神经系统渗透的理化和生物学因素提供了潜在的指导。