Summary
1) Miller’s literature review summarises treatments for IDH-mutant gliomas including direct isocitrate dehydrogenase (IDH) inhibitors, demethylating agents, PARP inhibitors, glutaminase inhibitor, DHODH inhibitor, CDK4/6 inhibitors, immune checkpoint inhibitors and vaccines. The article has a graph that shows the various points of attack where agents can compromise tumour growth. Each treatment strategy is discussed in one paragraph outlining the evidence. The article provides a great table listing trials targeting IDH-mutant gliomas. It is freely available but may require some effort to understand the medical/scientific language.
2) Ruda and colleagues give a good overview of how gliomas develop and differentiate. They describe the pathway of developing isocitrate dehydrogenase (IDH) inhibitors with a focus on the INDIGO trial and provide a list with current trials testing drugs for IDH-mutant glioma. The key points are (copied from the original article):
- Gliomas are the most common malignant primary brain tumours in adults, and they frequently contain mutations in the isocitrate dehydrogenase 1 (IDH1) or IDH2 gene. Mutant IDH produces the oncometabolite D-2-hydroxyglutarate (D-2-HG), which induces DNA and histone hypermethylation and interferes with immunity, thereby stimulating tumour growth.
- In preclinical models, selective inhibitors of mutant IDH were shown to decrease the production of D-2-HG, slow tumour growth and promote cellular differentiation.
- In early clinical trials, ivosidenib, a mutant IDH1 inhibitor, and vorasidenib, a brain-penetrant pan-mutant IDH inhibitor, were found to reduce D-2-HG concentrations and induce high rates of MRI-detectable glioma stabilization or response.
- The phase III INDIGO trial has shown superiority of vorasidenib over placebo in residual or recurrent non-enhancing grade 2 gliomas after surgery, thereby raising the prospect of delaying of chemoradiotherapy.
The abstract is freely available and a great summary. The full text is written for a medical/scientific audience.
Full text
The full text for Miller is attached below or available here.
The full text for Ruda et al is available for a fee here.
Research publication
Miller, J. J. (2022). Targeting IDH-Mutant Glioma. Neurotherapeutics, 19(6), 1724-1732. https://doi.org/10.1007/s13311-022-01238-3
Ruda, R., Horbinski, C., van den Bent, M., Preusser, M., & Soffietti, R. (2024). IDH inhibition in gliomas: from preclinical models to clinical trials. Nat Rev Neurol, 20(7), 395-407. https://doi.org/10.1038/s41582-024-00967-7