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New drug ONC201 for diffuse intrinsic pontine glioma: The right bullet for the right target!

Diffuse intrinsic pontine glioma (DIPG) is a form of intrinsic brainstem glioma that primarily affects children. DIPG is initially diagnosed based on clinical symptoms and imaging findings. These tumors are distinguished histologically by a heterogeneous population of cells with various genetic alterations and a high infiltrative capacity. DIPG is generally deadly because of its aggressive nature and critical location and is also resistant to the most eradicative treatment. Nevertheless, recent developments in therapeutics may considerably improve survival in these patients [1].

Will new breakthroughs shift the paradigm?

New drug ONC201 for diffuse intrinsic pontine glioma: The right bullet for the right target!

Only four drugs for high-grade gliomas have been approved in the last four decades, three of which are still in production (bevacizumab, lomustine, and carmustine). All of them were chosen to cross the blood-brain barrier as well as have resistance to chemotherapy and targeted therapies. Despite a few trials showing its activity, only one of these drugs, temozolomide, is licensed for pediatric high-grade gliomas in several countries. The situation is significantly worse in pediatric DIPG as temozolomide has not shown improved efficacy in DIPG treatment. Despite much advancement, the DIPG prognosis remains dark and dismal [2].

The mainstay of DIPG treatment primarily includes radiotherapy and chemotherapy, and in some cases surgical resection. DIPG presents a treatment challenge because surgical removal may be impractical due to tumor location, and chemotherapy and radiotherapy often fail due to tumor resistance. Preclinical research on DIPG has revealed various molecules with potential action; nevertheless, these drugs must be rigorously assessed utilizing cutting-edge technologies and, if valuable, can be made available to all patients globally [2].

Why the new drug-ONC201?

Dopamine receptor D2 is a G protein-coupled receptor that has emerged as a therapeutic target for gliomas and other tumors that overexpress this receptor. ONC201 is a small molecule antagonist of the dopamine receptor and an allosteric agonist of the ClpP (caseinolytic mitochondrial matrix peptidase proteolytic subunit).

In preclinical models of high-grade glioma, the drug crosses the blood-brain barrier and demonstrates p53-independent anti-cancer effectiveness. ONC201 can:

  • Stimulate the activating transcription factor 4 (ATF4)/C/EBP homologous protein (CHOP)-mediated integrated stress response pathway.

  • Inactivate Akt/ERK signaling (both Akt and ERK signaling are abnormally active in a variety of cancers and have long been targeted for cancer therapy).

  • Degrade c-myc, which plays an important function in controlling and proliferation of glioma stem cells.

ONC201 is a novel anti-tumor investigational therapeutic product now in phase II of the drug development process, with phase I study results indicating that it reaches faster micromolar concentrations in plasma and has a favorable tolerability profile in cancer patients. ONC201 is an imipridone that is used to treat a variety of cancers, and it induces an integrated stress response in tumor cells through downstream activation. ONC201 also has potent anti-tumor actions, including the prevention of malignant cell proliferation and apoptosis-like effects against a wide range of malignancies. The fact that ONC201 does not impact normal cells is a major advantage [3].

Shedding light on the progress of ONC201 in preclinical and clinical development

The first phase II clinical trial of oral ONC201 in adults with recurrent, bevacizumab-naive glioblastoma was reported using the suggested phase II oral dose of 625 mg once every 3 weeks (Identifier: NCT02525692). A 22-year-old woman with a thalamic glioma carrying a biopsy-proven H3 K27M mutation exhibited a near-complete durable response, involving complete reduction of the primary thalamic lesion [4].

Preclinical studies showed that glioma cell lines with the H3 K27M mutation were more sensitive to ONC201 cytotoxicity than wild-type counterparts, and this higher sensitivity was associated with increased dopamine receptor D2 expression. Based on these clinical and preclinical findings, a series of clinical trials to investigate ONC201 in patients with H3 K27M-mutated diseases such as DIPG were launched [3]. Two phase II clinical trials in adults with recurrent diffuse midline glioma (DIPG) treated with ONC201 monotherapy (Identifier: NCT03295396, NCT02525692) and the first phase I pediatric clinical trial of ONC201 were launched [4,5].

What can we learn from the ongoing ONC201 saga?

It is critical that more people participate in trials evaluating this drug for its potential to be proven, given how fatal gliomas and DIPG in particular are, and how treatment alternatives are only marginally effective. Although the results to date have not demonstrated a universal response to this treatment, accounts of individuals obtaining remission, clinical stability for years, and improvement in their symptoms. Furthermore, preliminary preclinical evidence suggests that combining ONC201 with other epigenetic modulators may be more effective in the setting of glioma, engendering ideas for further research.

In this context, the use of ONC201 as monotherapy in DIPG cases might be examined further; however, the efficacy of this drug in combination and comparison, to the mainstay of glioma treatment (resection, radiation, and temozolomide) should first be evaluated. With studies indicating that ONC201 enhances radiotherapy outcomes, a combination of radiotherapy and ONC201 may be the best option [3,6].

A positive future outlook

Although the cornerstones of therapy in DIPG are usually shown to be futile, innovative drugs are more commonly presented to patients with the expectation of remission. Data suggest that ONC201 may be especially successful for H3K27M mutant cancers, and its use is only anticipated to expand in the future. Although more research is needed, this drug may be added to DIPG treatment algorithms in the future.


1. Damodharan, S. et al. 'Diffuse Intrinsic Pontine Glioma: Molecular Landscape, Evolving Treatment Strategies and Emerging Clinical Trials'. Journal of Personalized Medicine. (2022) 12(5), 840. DOI: 10.3390/jpm12050840.

2. André, N. et al. 'Access to new drugs in paediatric oncology: can we learn from the ongoing ONC201 saga?'. The Lancet Oncology. (2023) 0(0). DOI: 10.1016/S1470-2045(23)00070-0.

3. Gardner, S.L. et al. 'Phase I dose escalation and expansion trial of single agent ONC201 in pediatric diffuse midline gliomas following radiotherapy'. Neurooncol Adv. (2022) 4(1), vdac143. DOI: 10.1093/noajnl/vdac143.

4. Chimerix. 'Oral ONC201 in Recurrent Glioblastoma, H3 K27M-mutant Glioma, and Diffuse Midline Glioma' [].

5. Chimerix. 'A Phase II, Open-label Study of ONC201 in Adults WithRecurrent High-grade Glioma' [].

6. Aloizou, A.-M. et al. 'ONC201 for Glioma Treatment: Adding an Important Weapon to Our Arsenal'. Neuroglia. (2023) 4(1), 28–33. DOI: 10.3390/neuroglia4010003.

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