Research Papers:
Imipridones ONC201/ONC206 + RT/TMZ triple (IRT) therapy reduces intracranial tumor burden, prolongs survival in orthotopic IDH-WT GBM mouse model, and suppresses MGMT
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Abstract
Lanlan Zhou1,2,3,4, Leiqing Zhang1,2,3,4, Jun Zhang1, Laura Jinxuan Wu1,4, Shengliang Zhang1,2,3,4, Andrew George1,2,3,4, Marina Hahn1,2,3,4, Howard P. Safran3,4,5, Clark C. Chen3,4,6, Attila A. Seyhan1,2,3,4, Eric T. Wong3,4,5,7 and Wafik S. El-Deiry1,2,3,4,5
1 Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02903, USA
2 Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
3 Joint Program in Cancer Biology, Brown University Health System and Brown University, RI 02903, USA
4 Legorreta Cancer Center at Brown University, RI 02903, USA
5 Department of Medicine, Hematology/Oncology Division, Brown University Health System and Brown University, RI 02903, USA
6 Department of Neurosurgery, Brown University Health and Brown University, RI 02903, USA
7 Departments of Medicine, Radiation Oncology, Neurosurgery and Neurology, Brown University, RI 02903, USA
Correspondence to:
Wafik S. El-Deiry, | email: | [email protected] |
Keywords: glioblastoma multiforme; IDH; ONC201; ONC206; MGMT; temozolomide; radiotherapy
Received: December 09, 2024 Accepted: March 13, 2025 Published: March 27, 2025
ABSTRACT
Glioblastoma remains a lethal brain tumor in adults with limited therapeutic options. TIC10/ONC201, a first-in-class imipridone we discovered, achieved meaningful therapeutic effects in phase I/II trials in patients with diffuse gliomas (DG’s) harboring H3K27M mutations, and currently the drug is in randomized phase III testing (ACTION trial; NCT05580562). ONC201 targets mitochondrial protease ClpP to disrupt oxidative phosphorylation and trigger the integrated stress response (ISR), TRAIL/DR5, and tumor cell death. While ONC201 and its analog ONC206 are undergoing clinical trials as single agents, there is limited information on their interactions with stand-of-care therapy. We show that ONC201 and ONC206 synergize with temozolomide (TMZ) and Radiotherapy (RT). ONC201 enhances TMZ- or RT-induced apoptosis, ISR and cytotoxicity. ClpP-silencing suppresses ONC201-induced cytotoxicity but not TMZ. Both ONC201 and ONC206 reduce expression of TMZ-resistance mediator MGMT observed in H3K27M-mutated DG cells following treatment with imipridones+TMZ. Cytokine profiling indicates distinct effects of ONC201 relative to TMZ treatment. These results suggest mechanisms underlying ONC201’s anti-tumoral activity are distinct from those associated with TMZ or RT with potential for synergy between these three treatments. Triple ONC201+RT+TMZ (IRT) therapy prolonged median survival to 123 days with tail on survival curve (3-of-7 mice alive beyond 200-days) in orthotopic U251 GBM model versus ONC201 (44-days; p = 0.000197), RT (63-days; p = 0.0012), TMZ (78-days; p = 0.0354), ONC201+RT (55-days; p = 0.0004), ONC201+TMZ (80-days; p = 0.0041) and RT+TMZ (103-days; p > 0.05). By 231-days, the only surviving mice were in IRT group. Our results support investigation of ONC201/ONC206 in combination with RT/TMZ (IRT) in GBM or H3K27M mutated DG therapy.

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