Almer Alyssa G, Rasmussen Samuel V, Kats Dina, Svalina Matthew N, Cole Bonnie L, Khani Mohammadreza, Chen Sonja, Cheshier Samuel H, Martin Bryn A, Berlow Noah E, Keller Charles
Children's Cancer Therapy Development Institute, Hillsboro, OR, USA.
Department of Pathology, Seattle Children's Hospital, Seattle, WA, USA.
Commun Med (Lond). 2025 May 28;5(1):206. doi: 10.1038/s43856-025-00925-4.
Leptomeningeal metastasis in medulloblastoma poses challenges for effective treatments due to the blood-brain barrier (BBB), which may be addressed through intrathecal or intraventricular drug delivery. However, the lack of pharmacokinetic modeling for pathological cerebrospinal fluid (CSF) geometries has limited the ability to predict effective intrathecal and intraventricular drug exposure.
A patient-specific computational fluid dynamics "in silico" trial was conducted to simulate CSF movement to examine the tumor microenvironment in terms of drug-target exposure over time following intraventricular delivery via Omaya Reservoir. Simultaneously, we conducted cellular adhesion experiments to test the therapeutic potential of IGF1R inhibition on metastasis under patient-specific flow conditions generated by computational analysis.
A 3-dimensional computational fluid dynamics (CFD) model based on patient-specific conditions was obtained to predict an efficacious drug concentration, providing guidance for therapeutic drug exposure at targeted sites. Microfluidic experiments for IGF1R inhibition of cellular adhesion showed the potential for reduced attachment of medulloblastoma to leptomeningeal cells to prevent metastasis.
This study offers insights from patient-specific in silico trials for the precision delivery of small-molecule drugs for the treatment of central nervous system (CNS) malignancies.
由于血脑屏障（BBB）的存在，髓母细胞瘤的软脑膜转移给有效治疗带来了挑战，可通过鞘内或脑室内给药来解决这一问题。然而，缺乏针对病理性脑脊液（CSF）几何形状的药代动力学模型限制了预测鞘内和脑室内药物有效暴露的能力。
进行了一项针对特定患者的计算流体动力学“虚拟”试验，以模拟脑脊液流动，通过奥马亚贮液器脑室内给药后，随时间推移研究药物靶点暴露方面的肿瘤微环境。同时，我们进行了细胞黏附实验，以测试在计算分析产生的特定患者血流条件下，抑制IGF1R对转移的治疗潜力。
获得了一个基于特定患者条件的三维计算流体动力学（CFD）模型，以预测有效药物浓度，为靶向部位的治疗性药物暴露提供指导。抑制IGF1R细胞黏附的微流控实验表明，髓母细胞瘤与软脑膜细胞的附着减少，具有预防转移的潜力。
本研究为小分子药物精准递送治疗中枢神经系统（CNS）恶性肿瘤的特定患者虚拟试验提供了见解。
