Cerebrospinal fluid penetration of targeted therapeutics in pediatric brain tumor patients

Abstract

Abstract 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.

Keywords

• Blood-brain barrier
• Cerebrospinal fluid
• Pharmacokinetics
• Ommaya reservoir
• High performances liquid chromatography mass spectrometry
• Targeted therapy