Effects of the DRD2/3 antagonist ONC201 and radiation in glioblastoma. (August 2021)

• Record Type: Journal Article
• Authors: He, Ling; Bhat, Kruttika; Ioannidis, Angeliki; Zhang, Le; Nguyen, Nhan T.; Allen, Joshua E.; Nghiemphu, Phioanh Leia; Cloughesy, Timothy F.; Liau, Linda M.; Kornblum, Harley I.; Pajonk, Frank
• Is Part Of: Radiotherapy and oncology. Volume 161(2021)
• Page Start: 140
• Page End: 147
• Publication Date: 2021-08
• Subjects: Glioblastoma -- Radiotherapy -- Dopamine receptor antagonist -- Transcriptome analyses -- Quiescent glioblastoma cells; Oncology -- Periodicals; Radiotherapy -- Periodicals; Tumors -- Periodicals; Medical Oncology -- Periodicals; Neoplasms -- radiotherapy -- Periodicals; Radiotherapy -- Periodicals; Radiothérapie -- Périodiques; Cancérologie -- Périodiques; Tumeurs -- Périodiques; Electronic journals; 616.9940642
• DOI: 10.1016/j.radonc.2021.05.027
• Languages: English
• ISSNs: 0167-8140

Abstract

Graphical abstract: 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 vitro and in vivo through suppression of GICs without increasing toxicity in mouse models of GBM. A clinical assessment of this novel combination therapy against GBM is further warranted.