image: Figure 1: ONC201 synergizes with RT. (A) Combination of ONC201 and RT treated GBM cell lines SNB19, T98G, and U251, and atypical teratoid rhabdoid tumor (ATRT: BT-12, BT-16) cell lines show treatment effects on cell viability. (B) Colony formation assays with ONC201 up to 4 μM alone or in combination with radiotherapy up to 8 Gy. Blue boxes are dose combinations that show synergy between ONC201 and radiation therapy. Combenefit was used to evaluate the interaction of multiple treatments on short term cell viability and long-term colony formation assay - synergistic combinations are denoted by a synergy score greater than zero. (C) Western blots were utilized to assess induction of PKA substrate phosphorylation, induction of ATF4 as a marker of ISR activation, and multiple markers of cell death such as cleaved PARP and cleaved Caspase 3 in treated brain tumor cells.
Credit: Copyright: © 2025 Zhou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
“Our findings demonstrate for the first time that IRT therapy combining ONC201 or ONC206 with RT and TMZ may be a safe and effective therapeutic strategy for GBM.”
BUFFALO, NY – April 4, 2025 – A new research paper was published in Oncotarget, Volume 16, on March 27, 2025, titled “Imipridones ONC201/ONC206 + RT/TMZ triple (IRT) therapy reduces intracranial tumor burden, prolongs survival in orthotopic IDH-WT GBM mouse model, and suppresses MGMT.”
Researchers from Brown University, led by first author Lanlan Zhou and corresponding author Wafik S. El-Deiry, have shown that combining a new class of drugs called imipridones with standard glioblastoma treatments significantly improves outcomes in mice. The study tested ONC201 and its analog ONC206 in combination with radiation therapy and the chemotherapy drug temozolomide (TMZ), a regimen referred to as IRT. This triple therapy slowed tumor growth and extended survival in a mouse model of glioblastoma, offering a potential new strategy for one of the most aggressive and treatment-resistant brain cancers.
Glioblastoma is a fast-growing brain tumor with a poor prognosis and limited treatment options. Standard care typically includes surgery, radiation, and TMZ, but most patients still face a short life expectancy. While ONC201 and ONC206 are currently being studied in clinical trials as single agents, there has been limited information on how they interact with standard therapies. This study is the first to show that both drugs work synergistically with radiation and TMZ, strengthening their overall effects.
The results showed that in both laboratory-grown tumor cells and mice, the triple therapy significantly slowed cancer cell growth, reduced tumor size, and prolonged survival compared to using any single or double treatment. Mice treated with IRT lived an average of 123 days, with some surviving more than 200 days—far longer than the 44 to 103 days observed with other treatment combinations. In addition to directly killing tumor cells, ONC201 and ONC206 lowered the expression of MGMT, a protein that helps tumors resist chemotherapy, making the treatment more effective.
The researchers also found that the triple therapy reshaped the tumor environment. It decreased levels of harmful molecules that promote tumor growth and immune evasion while increasing signals that activate the immune system. This dual action—directly attacking tumors and boosting immune responses—adds to the potential impact of this treatment approach.
“Overall, our preclinical findings support further exploration of the ONC201 and ONC206 IRT regimen as a potential treatment for GBM and diffuse gliomas with H3K27M mutations.”
While these findings are based on preclinical mouse models, they offer strong support for advancing this triple therapy to clinical trials. ONC201 and ONC206 are promising due to their ability to cross the blood-brain barrier and enhance the effects of standard treatment. This combination could lead to more effective therapies for glioblastoma and other hard-to-treat brain tumors.
Continue reading: DOI: https://doi.org/10.18632/oncotarget.28707
Correspondence to: Wafik S. El-Deiry — wafik@brown.edu
Keywords: cancer, glioblastoma multiforme, IDH, ONC201, ONC206, MGMT, temozolomide, radiotherapy
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About Oncotarget:
Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.
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Journal
Oncotarget
Method of Research
News article
Subject of Research
Animals
Article Title
Imipridones ONC201/ONC206 + RT/TMZ triple (IRT) therapy reduces intracranial tumor burden, prolongs survival in orthotopic IDH-WT GBM mouse model, and suppresses MGMT
Article Publication Date
27-Mar-2025
COI Statement
W.S.E-D. is a co-founder of Oncoceutics, Inc., a subsidiary of Chimerix. Dr. El-Deiry has disclosed his relationship with Oncoceutics/Chimerix and potential conflict of interest to his academic institution/employer and is fully compliant with NIH and institutional policy that is managing this potential conflict of interest.