Why now is an exciting time for Low Grade Gliomas

In my university years in the 1990s studying Biochemistry and later post-graduate education in Pharmaceutical R&D, I learned about proteins and enzymes, and possible approaches to discover and develop medicines that target the specific proteins and enzymes linked to diseases or metabolic dysfunction as a means of therapy and perhaps cure.  I learned how it was possible to screen thousands of possible chemical structures to find something that might block an enzyme by binding to it or interfering with it, and that over the course of decades an initial protein or enzyme of interest could start us down a path to identify a useful molecule and then develop it into a medicine that could be tested for safety and efficacy and later used to treat individuals and provide hope for a better quality of life.

I have reviewed my textbooks and find extraordinarily little in the way of functional or causal understanding of brain cancers.  It took until 2010 and later before researchers started to identify Isocitrate Dehydrogenase (IDH1 and IDH2) as being linked to Gliomas and other cancers, the impact of mutated forms of the enzyme and the role of metabolic products (metabolites) formed by mutated versions of the enzyme and identifying this mutated enzyme as a potential therapeutic target.  ^{(12) (13) (14)}  It was in the mid-2010s that we began to understand how cells carrying a mutated IDH had a metabolic advantage that also produced metabolites that could later accelerate cancerous cell proliferation and progress a low-grade glioma to a higher grade, faster growing cancer.  Think of this as my earlier analogy of a broken factory machine that now runs faster than normal and produces parts that are different from what the machine was meant to make.

Within a few years, research identified a way to construct small molecules that are a good match for the shape of the mutated IDH, such that they block the enzyme’s active site to slow down cell proliferation and reduce the rate of progression from low grade to high grade.  As a reversible inhibitor designed specifically to fit the mutated enzyme, this offered hope for a more elegant and targeted therapy that could reduce the burden of adverse events or side-effects of the older and less specific treatments available.  By 2017, Agios Pharmaceuticals, Inc. registered a patent to cover a family of such targeted therapies, describing a template for a molecule that can be re-designed to produce subtly different shapes that could benefit cancers with IDH mutations ⁽¹⁵⁾.  By December 2020, the France-headquartered global pharmaceutical company Servier acquired Agios Pharmaceuticals’ oncology business ⁽¹⁶⁾ including one molecule identified under a clinical identifier AG-881 and what will become known by its common name Vorasidenib.  Under a global multi-phase clinical trial known as INDIGO, Vorasidenib has been shown in a double-blinded phase 3 trial to extend Progression-free survival (PFS) in those taking Vorasidenib compared to those taking placebo, and to extend the Time to Next Intervention (TTNI) similarly ⁽¹⁷⁾.

I have no connection to Agios, Servier, or the clinical trial that will support new drug applications to Canada, USA, and Europe, but the results from this study give me hope.  After recently identifying mutated IDH as linked to cancers like mine, we already have potential therapeutic tools that can help lengthen duration spent with a higher quality of life, before needing other interventions that nearly guarantee undesirable side-effects and collateral damage that come with today’s decades-old brain cancer treatments.  The therapeutic potential and preliminary results from the INDIGO trial led the FDA to give Vorasidenib a breakthrough therapy designation, meaning that a New Drug Application (NDA) is given a fast-track review priority when submitted.  Fast-track status means that the FDA will reserve time for additional meetings with Servier while reviewing the application, making it possible to achieve an approval in the first half of 2024 if the submitted data supports the safety and efficacy needed for an approval.  This could mean that this new therapy could be available for patients soon, with potential for approvals and product launches in the US, Canada, and Europe, depending on Servier’s dossier submission approach and appropriate regional regulatory review and approval.

I am not putting all my hope into only Vorasidenib either, this approach of targeting the mutated IDH directly by using its unique shape as an exploitable weakness offers hope for treatment without the side effects of the current best available treatments.  The Patent ⁽¹⁵⁾ shows a template for a family of drugs that might offer positive results, but targeting the mutated IDH for what it is is only one of the things we can take advantage of.  The mutated IDH produces metabolites like 2-hydroxyglutarate (2-HG) that can further alter cell genetics and epigenetics that in turn promote further cancer progression. ⁽¹⁸⁾  Research is progressing into this metabolite, by instead targeting the mutated IDH for what it does.  While still quite early as a potential medicine, reducing the cellular harm from 2-HG could offer other therapeutic opportunities, such as research in bacterial enzymes that can correct 2-HG accumulation caused by mutations in IDH.  ⁽¹⁹⁾

In the first decade since discovering IDH as having a role in cancers like mine, it’s wildly encouraging and hopeful to see that we’re on the verge of having a real-world medicine that might improve the outlook for patients like me.  With modern, elegantly designed therapeutic tools capable of offering hope with a lower risk profile from side-effects, it really is an ideal time for those of us living with low grade gliomas.  There’s hope for new therapies that can extend quality of life before disease progression, meaning a longer PFS.  There’s hope that this longer PFS in turn leads to a longer TTNI, meaning patients like me can have longer before the next thing we need to face, whether that means more surgery, radiation, or chemotherapy, and with the recovery and side-effects that come with each intervention.  The hope for these new medicines gives hope that we might stop focusing on living from scan-to-scan in the space between our scheduled MRIs, and instead focus on just living.  While being diagnosed with a terminal illness like Oligodendroglioma isn’t ideal, these developments help me remind myself that being diagnosed as “alive” is also a terminal diagnosis.  They make it easier to focus on the living part of being alive, while letting Schrödinger’s cat (from my earlier reference) stay 100% alive, instead of focusing on how much longer it might survive.

My story will continue from here, where I’ll stay tuned in the progress of medicines like Vorasidenib and others that can take advantage of what we’ve only recently learned about IDH and other factors that contribute to the progression of brain cancers like mine.  It’s a perfect time to be alive with this diagnosis, and I’m excited to keep learning and seeing what the future has in store.

Works Cited

12. Garber, K. (2010). Oncometabolite? IDH1 Discoveries Raise Possibility of New Metabolism Targets in Brain Cancers and Leukemia. Journal of the National Cancer Institute, 102(13), 926-928. Retrieved 1 3, 2024, from https://academic.oup.com/jnci/article/102/13/926/872172

13. Yip, S., Butterfield, Y. S., Morozova, O., Chittaranjan, S., Blough, M. D., An, J., . . . Marra, M. A. (2012). Concurrent CIC mutations, IDH mutations, and 1p/19q loss distinguish oligodendrogliomas from other cancers. The Journal of Pathology, 226(1), 7-16. Retrieved 1 3, 2024, from https://ncbi.nlm.nih.gov/pubmed/22072542

14. Taylor, J., Chi, A. S., & Cahill, D. P. (2013). Tailored Therapy in Diffuse Gliomas: Using Molecular Classifiers to Optimize Clinical Management. Oncology, 27(6), 504. Retrieved 1 3, 2024, from https://www.cancernetwork.com/view/tailored-therapy-diffuse-gliomas-using-molecular-classifiers-optimize-clinical-management

15. Zhang, S. (2017, September 5). United States Patent No. 9,751,863 B2.

16. Servier Pharmaceuticals, LLC. (2020, Dec 21). Press Release. Retrieved from Servier home page: https://servier.com/en/newsroom/servier-to-acquire-agios-pharmaceuticals-oncology-business/

17. Mellinghoff, I. K., van den Bent, M. J., Blumenthal, D. T., Touat, M., Peters, K. B., Clarke, J., . . . Umemura, Y. (2023, August 17). Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma. New England Journal of Medicine, 389(7), 589 - 601. doi:10.1056/NEJMoa2304194

18. Ježek, P. (2020, Nov 1). 2-Hydroxyglutarate in Cancer Cells. Antioxidants & redox signaling, 33(13), 903 - 926. doi:10.1089/ars.2019.7902

19. Yin, W. J. (2023, Jul 20). A bacterial enzyme may correct 2-HG accumulation in human cancers. Frontiers in Oncology, 13:1235191. doi:10.3389/fonc.2023.1235191

20. Visser, O., Ardanaz, E., Botta, L., Sant, M., Tavilla, A., & Minicozzi, P. (2015). Survival of adults with primary malignant brain tumours in Europe; Results of the EUROCARE-5 study. European Journal of Cancer, 51(15), 2231-2241. doi: 10.1016/j.ejca.2015.07.032 Retrieved 1 3, 2024, from https://sciencedirect.com/science/article/pii/s0959804915007121