Highlights
- •Combined treatment of ONC201 and radiation exhibits anti-tumor effects on cells from primary and recurrent GBM.
- •Combined treatment significantly prolongs survival in vivo.
- •Combined treatment potentially targets the quiescent GBM cell population.
Abstract
Background
Glioblastoma (GBM) is the deadliest of all brain cancers in adults. The current standard-of-care
is surgery followed by radiotherapy and temozolomide, leading to a median survival
time of only 15 months. GBM are organized hierarchically with a small number of glioma-initiating
cells (GICs), responsible for therapy resistance and tumor recurrence, suggesting
that targeting GICs could improve treatment response. ONC201 is a first-in-class anti-tumor
agent with clinical efficacy in some forms of high-grade gliomas. Here we test its
efficacy against GBM in combination with radiation.
Methods
Using patient-derived GBM lines and mouse models of GBM we test the effects of radiation
and ONC201 on GBM self -renewal in vitro and survival in vivo.A possible resistance mechanism is investigated using RNA-Sequencing.
Results
Treatment of GBM cells with ONC201 reduced self-renewal, clonogenicity and cell viability in vitro. ONC201 exhibited anti-tumor effects on radioresistant GBM cells indicated by reduced
self-renewal in secondary and tertiary glioma spheres. Combined treatment of ONC201
and radiation prolonged survival in syngeneic and patient-derived orthotopic xenograft
mouse models of GBM. Subsequent transcriptome analyses after combined treatment revealed
shifts in gene expression signatures related to quiescent GBM populations, GBM plasticity,
and GBM stem cells.
Conclusions
Our findings suggest that combined treatment with the DRD2/3 antagonist ONC201 and
radiation improves the efficacy of radiation against GBM in vitroand in vivothrough suppression of GICs without increasing toxicity in mouse models of GBM. A
clinical assessment of this novel combination therapy against GBM is further warranted.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: June 04, 2021
Accepted:
May 30,
2021
Received in revised form:
May 23,
2021
Received:
November 23,
2020
Identification
Copyright
© 2021 Elsevier B.V. All rights reserved.
