Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Department of Neurosurgery, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte (CHULN), Lisboa, Portugal.
Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
Cell Rep Med. 2022 May 17;3(5):100623. doi: 10.1016/j.xcrm.2022.100623. Epub 2022 May 3.
Dissemination of cancer cells from primary tumors to the brain occurs in many cancer patients, increasing morbidity and death. There is an unmet medical need to develop translational platforms to evaluate therapeutic responses. Toward this goal, we established a library of 23 patient-derived xenografts (PDXs) of brain metastases (BMs) from eight distinct primary tumors. In vivo tumor formation correlates with patients' poor survival. Mouse subcutaneous xenografts develop spontaneous metastases and intracardiac PDXs increase dissemination to the CNS, both models mimicking the dissemination pattern of the donor patient. We test the FDA-approved drugs buparlisib (pan-PI3K inhibitor) and everolimus (mTOR inhibitor) and show their efficacy in treating our models. Finally, we show by RNA sequencing that human BMs and their matched PDXs have similar transcriptional profiles. Overall, these models of BMs recapitulate the biology of human metastatic disease and can be valuable translational platforms for precision medicine.
癌细胞从原发性肿瘤扩散到大脑的情况在许多癌症患者中都会发生，这增加了发病率和死亡率。目前，医学界迫切需要开发转化平台来评估治疗反应。为此，我们建立了一个包含 23 个源自 8 种不同原发性肿瘤的脑转移瘤（BM）患者来源异种移植物（PDX）的文库。体内肿瘤的形成与患者的不良生存相关。小鼠皮下异种移植物会自发转移，心脏内 PDX 会增加向中枢神经系统的扩散，这两种模型都模拟了供体患者的扩散模式。我们测试了 FDA 批准的药物 buparlisib（泛 PI3K 抑制剂）和 everolimus（mTOR 抑制剂），并证明它们在治疗我们的模型中的疗效。最后，我们通过 RNA 测序表明，人 BM 和其匹配的 PDX 具有相似的转录谱。总的来说，这些 BM 模型再现了人类转移性疾病的生物学特性，并且可以作为精准医学的有价值的转化平台。
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