AI Article Synopsis

  • Diffuse midline gliomas (DMG), particularly diffuse intrinsic pontine gliomas (DIPG), are highly lethal childhood cancers, with palliative radiotherapy offering limited survival benefits of 9-11 months.
  • ONC201, a drug that targets certain pathways in cancer cells, has shown potential effectiveness against DMG, but further research is needed to understand how different genetic mutations affect its response.
  • Studies indicate that DIPGs with PIK3CA mutations are more sensitive to ONC201, while those with TP53 mutations are resistant; combining ONC201 with the drug paxalisib can enhance treatment effectiveness by overcoming metabolic adaptations linked to these mutations.

Article Abstract

Unlabelled: Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9 to 11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA mutations showed increased sensitivity to ONC201, whereas those harboring TP53 mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992.

Significance: PI3K/Akt signaling promotes metabolic adaptation to ONC201-mediated disruption of mitochondrial energy homeostasis in diffuse intrinsic pontine glioma, highlighting the utility of a combination treatment strategy using ONC201 and the PI3K/Akt inhibitor paxalisib.

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-23-0186DOI Listing

Publication Analysis

Top Keywords

onc201
8
diffuse midline
8
diffuse intrinsic
8
intrinsic pontine
8
sensitivity onc201
8
metabolic adaptation
8
pi3k/akt signaling
8
pi3k/akt inhibitor
8
inhibitor paxalisib
8
onc201 combination
4

Similar Publications

Targeting Mitochondria in Glioma: New Hopes for a Cure.

Biomedicines

November 2024

Nervous System Medical Oncology Department, IRCCS Istituto delle Scienze Neurologiche di Bologna, 40139 Bologna, Italy.

Drugs targeting mitochondrial energy metabolism are emerging as promising antitumor therapeutics. Glioma treatment is extremely challenging due to the high complexity of the tumor and the high cellular heterogeneity. From a metabolic perspective, glioma cancer cells can be classified into the oxidative metabolic phenotype (mainly depending on mitochondrial respiration for energy production) and glycolytic phenotype or "Warburg effect" (mainly depending on glycolysis).

View Article and Find Full Text PDF

Real life data of ONC201 (dordaviprone) in pediatric and adult H3K27-altered recurrent diffuse midline glioma: Results of an international academia-driven compassionate use program.

Eur J Cancer

December 2024

Department of Pediatric and Adolescent Oncology, Gustave Roussy, Villejuif, France; Team Genomics and Oncogenesis of Brain Tumors, INSERM U981, Paris Saclay University, Villejuif, France.

Introduction: H3K27-altered diffuse midline gliomas (DMG) have limited therapeutic options and a very poor prognosis. Encouraging responses were observed in early clinical trials with ONC201. As ONC201 was unavailable in Europe, a compassionate use program supported by the French Authorities was launched for patients at progression after standard of care radiotherapy.

View Article and Find Full Text PDF

Our ongoing research focuses on the development of new imipridone derivatives. We aim to design compounds that can completely and selectively eradicate cancer cells after relatively short treatment. We have synthetized systematically designed novel hybrids and evaluated their antiproliferative activity against PANC-1 and Fadu cell lines.

View Article and Find Full Text PDF

Development of a pediatric oral solution of ONC201 using nicotinamide to enhance solubility and stability.

Int J Pharm

December 2024

Department of clinical pharmacy, Gustave Roussy Cancer Campus, Villejuif 94800, France; Université Paris-Saclay, CNRS, Institut des Sciences Moléculaires d'Orsay, Orsay 91405, France.

Diffuse intrinsic pontine glioma (DIPG) poses a significant treatment challenge in pediatric patients due to its aggressive nature and difficulty in crossing the blood-brain barrier with effective therapies. ONC201 (dordaviprone) shows promises in inducing apoptosis in cancer cells but suffers from poor water solubility and stability issues. Moreover, conventional solubilizing agents acceptable in formulations intended for adult patients are not suitable for pediatric use.

View Article and Find Full Text PDF

Dordaviprone (ONC201) is a novel, orally administered, anti-cancer, small molecule imipridone with demonstrated antitumor effects in patients with glioma. Dordaviprone in vitro solubility is significantly reduced at pH >4.5.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!