Combo Drug delivering a knockout blow to resistant glioma cancer cells
2023-05-24
Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal of childhood cancers primarily occurring in young children.
Professor Matt Dun and his Newcastle University team have been working to identify how the drug ONC201 is working to kill DIPG cancer cells. This is done by determining the molecular pathways that the cancer cells within the brain tumour are affecting.
With investment from The Kids’ Cancer Project the team’s DIPG research has identified genetic markers, or mutations, that can be used as “biomarkers of response” to the drug. This means clinicians may one day be able to screen patients to identify those children who will potentially respond to treatment and those who won’t. In doing so kids who won’t benefit from this particular treatment will not be put through needless therapy.
As with all targeted drugs, cancer cells can adapt and survive by using alternate signalling pathways. This is why resistance to treatment and/or cancer relapse can occur. However, when only treated with the ONC201 drug the DIPG cells ‘escape’ its effect by using the P13-kinase (PI3K) molecular pathway which is essential for the growth of cancer cells.
Paxalisib is a medication that targets this alternate route and, when used in combination with ONC201, has proved highly effective in killing errant cancer cells. This drug combination is now in early phase clinical trials for DIPG.
This Australian study adds weight to how the ONC201 and paxalisib work on their own and in combination. The study also guides clinical practice in terms of which DIPG patients will benefit from the drug combination as well as those that won’t.
Professor Matt Dun, who sadly lost his own four-year-old daughter to DIPG, has extended his thanks to The Kids' Cancer Project and its donor and partner community stating that, “We are immensely thankful to organisations such as yours; the research required to change outcomes for DIPG/DMG patients, and their families just would not occur in your absence.
Thank you to all those who gave so this work could be carried out. Supporting our research through grant funding since 2022 made detailed work possible. The Kids’ Cancer Project support is part of this research achievement.”
Professor Dun’s research study has recently been published in Cancer Research a peer-reviewed medical journal published by the American Association for Cancer Research.
Reporting the mechanisms behind response to 'ONC201', and its effect in combination with 'paxalisib', the paper details the team’s dedicated efforts to bring promising therapies to clinical trial. Proudly, this was done within just three years, with research underpinning PNOC022 (Combination Therapy for the Treatment of Diffuse Midline Glioma - NCT05009992), opening in the US in 2021, Australia in 2022, and now recruiting in New Zealand, Switzerland, The Netherlands and Israel.
Professor Dun and the Newcastle University team are currently studying how to further improve response to ONC201 and paxalisib, as well as the design and development of immune-based approaches, novel anti-DMG therapeutics and a major multi-omic study aiming to revolutionise DIPG/DMG tumour classification (and hence treatment development/selection) directly funded by The Kids’ Cancer Project.