Overcoming translational barriers in H3K27-altered diffuse midline glioma: Increasing the drug-tumor residence time.
Overcoming translational barriers in H3K27-altered diffuse midline glioma: Increasing the drug-tumor residence time.
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DOI：
10.1093/noajnl/vdad033
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发表时间：
2023-01
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H3K27基因突变的弥漫性中线胶质瘤(DMG)是最致命的儿童脑瘤；尽管进行了密集的研究工作，但到目前为止所有的临床试验都失败了。这是因为我们选择了错误的药物吗？或者，药物释放和其他药代动力学变量是否在起作用？我们假设答案可能是一种组合，其中优化可能导致急需的新治疗方法。我们使用体外药物筛选、患者样本和shRNA敲除模型来确定DMG中上调的靶点。选择了一种具有翻译潜力的单一小分子蛋白激酶抑制剂，用于患者来源的异种移植物(PDX)和基因工程小鼠模型(GEMM)的系统和直接局部给药。在非荷瘤大鼠体内进行了药代动力学研究。极光激酶(AK)抑制剂在DMG药物筛选中显示出很强的抗肿瘤作用。更多的体外研究证实了AK对DMG生存的重要性。全身给药在皮下PDX模型中显示出良好的前景，但在颅内GEMM和PDX模型中不显示前景。通过对流增强递送(CED)向肿瘤内反复局部给药同样无效，药代动力学研究显示阿利色布从脑中迅速清除。为了增加药物到肿瘤的滞留时间，持续7天以上的CED改善了药物在啮齿动物脑干中的滞留，并显著延长了原位PDX和GEMM的存活时间。这些研究为通过延长CED作为DMG的一种有价值的治疗策略来增加药物-肿瘤滞留时间提供了证据。
H3K27-altered diffuse midline glioma (DMG) is the deadliest pediatric brain tumor; despite intensive research efforts, every clinical trial to date has failed. Is this because we are choosing the wrong drugs? Or are drug delivery and other pharmacokinetic variables at play? We hypothesize that the answer is likely a combination, where optimization may result in a much needed novel therapeutic approach. We used in vitro drug screening, patient samples, and shRNA knockdown models to identify an upregulated target in DMG. A single small molecule protein kinase inhibitor with translational potential was selected for systemic and direct, loco-regional delivery to patient-derived xenografts (PDX) and genetically engineered mouse models (GEMM). Pharmacokinetic studies were conducted in non-tumor bearing rats. Aurora kinase (AK) inhibitors demonstrated strong antitumor effects in DMG drug screens. Additional in vitro studies corroborated the importance of AK to DMG survival. Systemic delivery of alisertib showed promise in subcutaneous PDX but not intracranial GEMM and PDX models. Repeated loco-regional drug administration into the tumor through convection-enhanced delivery (CED) was equally inefficacious, and pharmacokinetic studies revealed rapid clearance of alisertib from the brain. In an effort to increase the drug to tumor residence time, continuous CED over 7 days improved drug retention in the rodent brainstem and significantly extended survival in both orthotopic PDXs and GEMMs. These studies provide evidence for increasing drug-tumor residence time of promising targeted therapies via extended CED as a valuable treatment strategy for DMG.