Human cerebrospinal fluid affects chemoradiotherapy sensitivities in tumor cells from patients with glioblastoma

Brett W. Stringer, Manam Inushi De Silva, Zarina Greenberg, Alejandra Noreña Puerta, Robert Adams, Bridget Milky, Michael Zabolocki, Mark van den Hurk, Lisa M. Ebert, Christine Fairly Bishop, Simon J. Conn, Ganessan Kichenadasse, Michael Z. Michael, Rebecca J. Ormsby, Santosh Poonoose, Cedric Bardy

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)eadf1332
JournalScience Advances
Volume9
Issue number43
DOIs
Publication statusPublished or Issued - 27 Oct 2023

ASJC Scopus subject areas

  • General

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