Effects of the DRD2/3 antagonist ONC201 and radiation in glioblastoma.

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-renewalin vitro and survivalin vivo.A possible resistance mechanism is investigated using RNA-Sequencing.

RESULTS:

Treatment of GBM cells with ONC201 reduced self-renewal, clonogenicity and cell viabilityin 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 GBMin vitroandin 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.

• Authors: Ling He, Kruttika Bhat, Angeliki Ioannidis, Le Zhang, Nhan T Nguyen, Joshua E Allen, Phioanh Leia Nghiemphu, Timothy F Cloughesy, Linda M Liau, Harley I Kornblum, Frank Pajonk
• Journal: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology (Radiother Oncol) Vol. 161 Pg. 140-147 (08 2021) ISSN: 1879-0887 [Electronic] Ireland
• PMID: 34097975 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• DRD2 protein, human
• DRD2 protein, mouse
• Imidazoles
• Pyridines
• Pyrimidines
• Receptors, Dopamine D2
• TIC10 compound

Topics

• Adult
• Animals
• Brain Neoplasms (radiotherapy)
• Cell Line, Tumor
• Glioblastoma (radiotherapy)
• Humans
• Imidazoles
• Mice
• Neoplasm Recurrence, Local
• Pyridines
• Pyrimidines
• Receptors, Dopamine D2
• Xenograft Model Antitumor Assays