South Australian Health and Medical Research Institute (SAHMRI), Laboratory for Human Neurophysiology and Genetics, Adelaide, SA, Australia.
Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.
Sci Adv. 2023 Oct 27;9(43):eadf1332. doi: 10.1126/sciadv.adf1332. Epub 2023 Oct 25.
Cancers in the central nervous system resist therapies effective in other cancers, possibly due to the unique biochemistry of the human brain microenvironment composed of cerebrospinal fluid (CSF). However, the impact of CSF on cancer cells and therapeutic efficacy is unknown. Here, we examined the effect of human CSF on glioblastoma (GBM) tumors from 25 patients. We found that CSF induces tumor cell plasticity and resistance to standard GBM treatments (temozolomide and irradiation). We identified nuclear protein 1 (NUPR1), a transcription factor hampering ferroptosis, as a mediator of therapeutic resistance in CSF. NUPR1 inhibition with a repurposed antipsychotic, trifluoperazine, enhanced the killing of GBM cells resistant to chemoradiation in CSF. The same chemo-effective doses of trifluoperazine were safe for human neurons and astrocytes derived from pluripotent stem cells. These findings reveal that chemoradiation efficacy decreases in human CSF and suggest that combining trifluoperazine with standard care may improve the survival of patients with GBM.
中枢神经系统的癌症对其他癌症有效的治疗方法有抵抗力，这可能是由于由脑脊液 (CSF) 组成的人脑微环境的独特生物化学特性所致。然而，CSF 对癌细胞和治疗效果的影响尚不清楚。在这里，我们研究了人 CSF 对来自 25 名患者的脑胶质瘤 (GBM) 肿瘤的影响。我们发现 CSF 诱导肿瘤细胞可塑性并对标准 GBM 治疗（替莫唑胺和顺铂）产生抗性。我们确定核蛋白 1 (NUPR1)，一种阻碍铁死亡的转录因子，作为 CSF 中治疗抗性的介质。用重新定位的抗精神病药三氟拉嗪抑制 NUPR1，增强了对 CSF 中对化疗和放疗有抗性的 GBM 细胞的杀伤作用。三氟拉嗪的相同化学有效剂量对源自多能干细胞的人神经元和星形胶质细胞是安全的。这些发现表明，在人 CSF 中化学放射疗法的疗效降低，并表明将三氟拉嗪与标准治疗相结合可能改善 GBM 患者的生存率。
