학술논문
Human cerebrospinal fluid affects chemoradiotherapy sensitivities in tumor cells from patients with glioblastoma.
Document Type
Article
Author
Stringer, Brett W.; De Silva, Manam Inushi; Greenberg, Zarina; Noreña Puerta, Alejandra; Adams, Robert; Milky, Bridget; Zabolocki, Michael; van den Hurk, Mark; Ebert, Lisa M.; Bishop, Christine Fairly; Conn, Simon J.; Kichenadasse, Ganessan; Michael, Michael Z.; Ormsby, Rebecca J.; Poonoose, Santosh; Bardy, Cedric
Source
Subject
*CENTRAL nervous system cancer
*PLURIPOTENT stem cells
*GLIOBLASTOMA multiforme
*RHINORRHEA
*CHEMORADIOTHERAPY
*NUCLEAR proteins
*CEREBROSPINAL fluid examination
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Language
ISSN
2375-2548
Abstract
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. [ABSTRACT FROM AUTHOR]