Synergistic Effects of the DRD2/3 Antagonist ONC201 and Radiation in Glioblastoma

Abstract

BackgroundGlioblastoma (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, responsible for therapy resistance and tumor recurrence, suggesting that targeting glioma-initiating cells 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.MethodsUsing 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.ResultsTreatment 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 with 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.ConclusionsOur 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.Key points- Combined treatment of ONC201 and radiation exhibit 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 populationImportance of the StudyThe survival rates for patients with GBM are unacceptably low and novel treatment approaches are needed. This study provides evidence that a combination of radiation and the dopamine receptor antagonist ONC201 significantly prolongs survival in mouse models of glioma.

Exploring neuroadaptive cellular pathways in chronic morphine exposure: An in‐vitro analysis of cabergoline and Mdivi‐1 co‐treatment effects on the autophagy–apoptosis axis

“…Innovations in GBM treatment highlight the effectiveness of DRD2/3 antagonists combined with radiation therapy, and the role of D2 activation in tumor growth and stem‐cell‐like transitions 52,53 . Our study provides the first evidence of D2R expression increase in human GBM cell lines due to chronic morphine treatment.…”

“…51 Innovations in GBM treatment highlight the effectiveness of DRD2/3 antagonists combined with radiation therapy, and the role of D2 activation in tumor growth and stem-cell-like transitions. 52,53 Our study provides the first evidence of D2R expression increase in human GBM cell lines due to chronic morphine treatment. Morphine derivatives, commonly used in GBM pain management, do not exacerbate tumorigenesis or radio-resistance in GBM cells, as indicated by studies on MTD.…”

Dopamine Receptors in Cancer: Are They Valid Therapeutic Targets?

“…29 In mouse models, ONC201 crosses the blood-brain barrier, inhibiting GBM growth and increasing the median survival time when combined with radiotherapy. 29,64 To date, clinical trials using ONC201 have shown signs of efficacy in biomarker-defined recurrent GBM patients, 64,65 as well as in pediatric and adult H3 K27M-mutant glioma. [65][66][67] Noteworthy, ONC201 is also in Phase II clinical trials for AML, 68,69 breast cancer, 69,70 colorectal cancer, 69,71 lung cancer, 71 endometrial cancer, [69][70][71] and multiple myeloma.…”

“…2,62 DRD2 silencing, 62 but also DRD4 silencing 32 or trifluoperazine treatment, 53 reduces the clonogenicity of GBM cells, an in vitro subrogate measurement of the CSC content. ONC201 reduces the self-renewal of glioblastoma CSCs in vitro 64 and inhibits the proliferation of CSCs in 3D neurospheres culture established from freshly isolated human glioblastoma tumors. 29 Similarly, the DRD4-selective antagonists L-741742 and PNU-96415E decrease GBM stem cell viability and block their clonogenicity but do not affect normal neural a 2C-AR: 7.4 # a 2B -AR: 7.2 # 5-HT 2C : 7.0 # 5-HT 1A : 6.9 (partial) 5-HT 2A : 6.9 # 5-HT 2B : 6.9 # a 2A -AR: 6.9 (partial) NSCLC 50 (continued) stem cells.…”