Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; ChEM-H, Stanford University, Stanford, CA, USA.
Department of Medicine, Institute for Genomics and Systems Biology, University of Chicago, Chicago, IL, USA.
Cell Rep. 2021 Nov 2;37(5):109957. doi: 10.1016/j.celrep.2021.109957.
The highly lethal brain cancer glioblastoma (GBM) poses a daunting challenge because the blood-brain barrier renders potentially druggable amplified or mutated oncoproteins relatively inaccessible. Here, we identify sphingomyelin phosphodiesterase 1 (SMPD1), an enzyme that regulates the conversion of sphingomyelin to ceramide, as an actionable drug target in GBM. We show that the highly brain-penetrant antidepressant fluoxetine potently inhibits SMPD1 activity, killing GBMs, through inhibition of epidermal growth factor receptor (EGFR) signaling and via activation of lysosomal stress. Combining fluoxetine with temozolomide, a standard of care for GBM, causes massive increases in GBM cell death and complete tumor regression in mice. Incorporation of real-world evidence from electronic medical records from insurance databases reveals significantly increased survival in GBM patients treated with fluoxetine, which was not seen in patients treated with other selective serotonin reuptake inhibitor (SSRI) antidepressants. These results nominate the repurposing of fluoxetine as a potentially safe and promising therapy for patients with GBM and suggest prospective randomized clinical trials.
高度致命的脑癌胶质母细胞瘤 (GBM) 构成了严峻的挑战，因为血脑屏障使潜在可用药的扩增或突变致癌蛋白相对难以接近。在这里，我们确定神经鞘磷脂磷酸二酯酶 1 (SMPD1) 是一种调节神经鞘磷脂转化为神经酰胺的酶，是 GBM 中的一个可操作的药物靶点。我们表明，高度穿透血脑屏障的抗抑郁药氟西汀通过抑制表皮生长因子受体 (EGFR) 信号和激活溶酶体应激，强烈抑制 SMPD1 活性，从而杀死 GBM。将氟西汀与替莫唑胺联合使用，替莫唑胺是 GBM 的标准治疗方法，可导致 GBM 细胞大量死亡，并在小鼠中完全消退肿瘤。从保险数据库的电子病历中纳入真实世界的证据表明，接受氟西汀治疗的 GBM 患者的生存率显著提高，而接受其他选择性 5-羟色胺再摄取抑制剂 (SSRI) 抗抑郁药治疗的患者则没有这种情况。这些结果提名氟西汀作为一种潜在安全且有前途的治疗 GBM 患者的药物，并建议进行前瞻性随机临床试验。
