A paucity of chemotherapeutic options for metastatic brain cancer limits patient survival and portends poor clinical outcomes. Using a CNS small-molecule inhibitor library of 320 agents known to be blood-brain barrier permeable and approved by the FDA, we interrogated breast cancer brain metastasis vulnerabilities to identify an effective agent. Metixene, an antiparkinsonian drug, was identified as a top therapeutic agent that was capable of decreasing cellular viability and inducing cell death across different metastatic breast cancer subtypes. This agent significantly reduced mammary tumor size in orthotopic xenograft assays and improved survival in an intracardiac model of multiorgan site metastases. Metixene further extended survival in mice bearing intracranial xenografts and in an intracarotid mouse model of multiple brain metastases. Functional analysis revealed that metixene induced incomplete autophagy through N-Myc downstream regulated 1 (NDRG1) phosphorylation, thereby leading to caspase-mediated apoptosis in both primary and brain-metastatic cells, regardless of cancer subtype or origin. CRISPR/Cas9 KO of NDRG1 led to autophagy completion and reversal of the metixene apoptotic effect. Metixene is a promising therapeutic agent against metastatic brain cancer, with minimal reported side effects in humans, which merits consideration for clinical translation.

中文翻译：

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Metixene 是转移性癌症和脑转移临床前模型中的不完全自噬诱导剂


转移性脑癌化疗方案的缺乏限制了患者的生存并预示着不良的临床结果。我们使用由 320 种已知可渗透血脑屏障且经 FDA 批准的中枢神经系统小分子抑制剂库组成的中枢神经系统小分子抑制剂库，研究了乳腺癌脑转移的脆弱性，以确定有效的药物。 Metixene 是一种抗帕金森病药物，被认为是一种顶级治疗药物，能够降低不同转移性乳腺癌亚型的细胞活力并诱导细胞死亡。在原位异种移植试验中，该药物显着减小了乳腺肿瘤的大小，并提高了多器官部位转移的心内模型中的存活率。 Metixene 进一步延长了颅内异种移植小鼠和颈动脉内多发脑转移小鼠模型的生存期。功能分析显示，metixene 通过 N-Myc 下游调节 1 (NDRG1) 磷酸化诱导不完全自噬，从而导致原发细胞和脑转移细胞中 caspase 介导的细胞凋亡，无论癌症亚型或起源如何。 NDRG1 的 CRISPR/Cas9 KO 导致自噬完成并逆转 metixene 凋亡效应。 Metixene 是一种很有前途的治疗转移性脑癌的药物，据报道对人类的副作用极小，值得考虑进行临床转化。