Exclusion of brain metastases from clinical trials is a major cause of the limited therapeutic options for this growing population of cancer patients. Here, we report a medium-throughput drug-screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to brain metastasis, we identified several hits from a library of FDA approved inhibitors and others being tested in clinical trials. A blood-brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to organotypic cultures with metastases treated with the chaperone inhibitor revealed novel biomarkers in human brain metastasis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples. We envision that METPlatform could be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere.

中文翻译：

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基于器官型文化的药物筛选平台可识别可预防局部复发并治疗已建立的脑转移的脆弱性

从临床试验中排除脑转移是导致癌症患者不断增长的有限治疗选择的主要原因。在这里，我们报告了基于器官型培养的中等通量药物筛选平台（METPlatform），该平台可以评估针对原位生长的转移的抑制剂。通过将这种方法应用于脑转移，我们从FDA批准的抑制剂库中发现了一些命中数据，而其他命中也在临床试验中进行了测试。血脑屏障可渗透的HSP90抑制剂在该疾病的临床相关阶段显示出对小鼠和人脑转移的高效力，包括神经外科手术后局部复发的新型模型。此外，原位蛋白质组学分析应用于伴有伴侣蛋白抑制剂治疗的转移的器官型培养物中，揭示了人脑转移中新的生物标志物和抗药性的作用机制。我们的工作验证了METPlatform是整合了药物筛选和与人类样品完全兼容的无偏渗透性方法的转移研究的有效资源。我们设想，可以将METPlatform建立为临床相关策略，以个性化管理大脑和其他部位的转移性疾病。