One of IronMatts’ 2015 grant recipients, Dr. Javad Nazarian, was published in Neuro-Oncology’s September 2022 issue. You can read the full article here.
This study defined the molecular mechanism and target-engagement of ONC201 and ONC206 and presented ONC206 as a novel and effective drug for targeting DMG bioenergetics. The results supported the initiation of two clinical trials (NCT05009992, NCT04732065). Identified biomarkers of drug-target engagement will have clinical importance for monitoring response to therapy.
This study was important because pediatric brainstem gliomas (BSGs) account for 15% of all brain tumors in children. Diffuse intrinsic pontine gliomas (DIPGs) are the most aggressive and high-grade tumors among BSGs with the peak age of onset around 6-7 years. Children diagnosed with DIPG have less than 90% chance of survival within two years of diagnosis.
In his application, Dr. Nazarian reported that advances in DIPG research had identified genetic aberrations associated with these tumors. These include mutations in histone 3.3 and p53 genes and activation of tumor associated signaling pathways. One of the most important of such is PDGFR mediated pathway, which was found to be stabilized by transmembrane protein NG2.
In adult gliomas, NG2 expressing cells often co-express PDGFR , where NG2 contributes to the transformation of precursor cells into glioma. Despite the potential role of NG2 in adult gliomas, the role of NG2 expression had not been previously studied in pediatric gliomas.
“In our lab, using postmortem DIPG samples and cultured cells, we observed increased NG2 levels, specifically in tumor samples. In addition, we found that NG2 in DIPG tumor samples and primary tumor cells are negatively regulated by microRNA 129-2 (miR129-2) to decrease NG2 levels. Thus it is valuable to examine if miR129-2 can be used as a therapeutic molecule to target NG2 in DIPGs,” he said.
In his study, Dr. Nazarian found that targeting mitochondrial metabolism and ISR activation effectively impairs DMG tumorigenicity. These results supported the initiation of two pediatric clinical trials (NCT05009992, NCT04732065).
- Imipridones target DMG cell bioenergetics and activate the integrated stress response.
- Imipridone-induced lineage shift from OPC to AC is novel, requiring further investigation.
- Our data provides a foundation for new clinical trials using ONC206 for the treatment of DMGs.
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