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 the unmet clinical need of brain metastasis, we identified several vulnerabilities. Among them, 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 metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastasis, which includes biomarkers of poor prognosis 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 compatible with human samples. Thus, this clinically relevant strategy is aimed to personalize the management of metastatic disease in the brain and elsewhere.

中文翻译：

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基于器官培养的临床兼容药物筛选平台可识别预防和治疗脑转移的弱点

我们报告了一个基于器官培养物的中等通量药物筛选平台 (METPlatform)，该平台允许评估针对原位生长的转移瘤的抑制剂。通过将这种方法应用于脑转移未满足的临床需求，我们发现了几个漏洞。其中，一种可透过血脑屏障的 HSP90 抑制剂在疾病的临床相关阶段显示出对小鼠和人类脑转移的高效力，包括神经外科手术后局部复发的新模型。此外，现场应用于用伴侣抑制剂治疗的转移瘤的蛋白质组学分析揭示了脑转移瘤的新分子程序，其中包括预后不良的生物标志物和可操作的耐药机制。我们的工作验证了 METPlatform 作为转移研究的有效资源，整合了药物筛选和与人类样本兼容的无偏组学方法。因此，这种临床相关策略旨在个性化处理大脑和其他部位的转移性疾病。