TY - JOUR
T1 - Human cerebrospinal fluid affects chemoradiotherapy sensitivities in tumor cells from patients with glioblastoma
AU - Stringer, Brett W.
AU - De Silva, Manam Inushi
AU - Greenberg, Zarina
AU - Puerta, Alejandra Noreña
AU - Adams, Robert
AU - Milky, Bridget
AU - Zabolocki, Michael
AU - van den Hurk, Mark
AU - Ebert, Lisa M.
AU - Bishop, Christine Fairly
AU - Conn, Simon J.
AU - Kichenadasse, Ganessan
AU - Michael, Michael Z.
AU - Ormsby, Rebecca J.
AU - Poonoose, Santosh
AU - Bardy, Cedric
N1 - Publisher Copyright:
© 2023 The Authors.
PY - 2023/10
Y1 - 2023/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85175217419&partnerID=8YFLogxK
U2 - 10.1126/sciadv.adf1332
DO - 10.1126/sciadv.adf1332
M3 - Article
C2 - 37878712
AN - SCOPUS:85175217419
SN - 2375-2548
VL - 9
JO - Science Advances
JF - Science Advances
IS - 43
M1 - eadf1332
ER -