Vorasidenib: A case study in bench-to-bedside translational research

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Spencer Maingi

Identifying IDH mutations and their function

In 2008, researchers studying brain tumors discovered something surprising. Patients with “secondary glioblastoma”, a uniformly lethal cancer that arises from a prior, less aggressive brain tumor (“low-grade glioma”), frequently had mutations in their tumor in the gene isocitrate dehydrogenase 1 (IDH1).¹ Even more interesting was the fact that all of the patients had a mutation in the exact same spot of the gene. The mutation changed residue 132 in the IDH1 protein from an arginine to another amino acid (IDH1 132R). This “hotspot” mutation was deemed to play a critical role in the normal function of IDH1, and researchers posited that it may be a potential driver in the development of these aggressive brain tumors. 

Just a year later scientists found that these same IDH1 R132 mutations were found in roughly over 70% of lower-grade gliomas, many of which frequently progressed into the more aggressive secondary glioblastomas.² Notably, they also probed for mutations in the gene isocitrate dehydrogenase 2 (IDH2), an isoform of IDH1 that fulfills a similar biological role. Their findings indicated that in the tumors that lacked the IDH1 R132 mutation, many of them had a hotspot mutation in the analogous amino acid in IDH2: the arginine residue at position 172 (IDH2 R172). So groundbreaking was this new genetic data that it would end up reshaping how low-grade brain tumors were diagnosed based on whether a tumor had an IDH1 or IDH2 mutation.

What was it about mutant IDH1 and IDH2 that induced a brain tumor? Compared to their normal counterparts, IDH1 and IDH2 with mutations in the arginine amino acid resulted in accumulation of a compound called 2-hydroxyglutarate (2-HG). This “oncometabolite” was discovered to cause widespread changes in the genetic landscape and microenvironment of cells in the brain, ultimately resulting in a less-differentiated cellular state that could transform healthy cells into cancerous ones.  

Identifying IDH mutations and their function

In 2008, researchers studying brain tumors discovered something surprising. Patients with “secondary glioblastoma”, a uniformly lethal cancer that arises from a prior, less aggressive brain tumor (“low-grade glioma”), frequently had mutations in their tumor in the gene isocitrate dehydrogenase 1 (IDH1).¹ Even more interesting was the fact that all of the patients had a mutation in the exact same spot of the gene. The mutation changed residue 132 in the IDH1 protein from an arginine to another amino acid (IDH1 132R). This “hotspot” mutation was deemed to play a critical role in the normal function of IDH1, and researchers posited that it may be a potential driver in the development of these aggressive brain tumors. 

Just a year later scientists found that these same IDH1 R132 mutations were found in roughly over 70% of lower-grade gliomas, many of which frequently progressed into the more aggressive secondary glioblastomas.² Notably, they also probed for mutations in the gene isocitrate dehydrogenase 2 (IDH2), an isoform of IDH1 that fulfills a similar biological role. Their findings indicated that in the tumors that lacked the IDH1 R132 mutation, many of them had a hotspot mutation in the analogous amino acid in IDH2: the arginine residue at position 172 (IDH2 R172). So groundbreaking was this new genetic data that it would end up reshaping how low-grade brain tumors were diagnosed based on whether a tumor had an IDH1 or IDH2 mutation.

What was it about mutant IDH1 and IDH2 that induced a brain tumor? Compared to their normal counterparts, IDH1 and IDH2 with mutations in the arginine amino acid resulted in accumulation of a compound called 2-hydroxyglutarate (2-HG). This “oncometabolite” was discovered to cause widespread changes in the genetic landscape and microenvironment of cells in the brain, ultimately resulting in a less-differentiated cellular state that could transform healthy cells into cancerous ones.  

Developing IDH-specific inhibitors: in the lab

After discovering these mutations, scientists went to work finding a molecule that could inhibit the rouge IDH proteins in glioma cells. Remarkably, just five years after discovering the IDH1 and IDH2 hotspot mutations in low-grade gliomas, a paper in Science reported a novel compound (AGI-5198) that specifically inhibited mutant IDH1 so well that it drastically decreased production of 2-HG in mouse models of gliomas.³ Notably, AGI-5198 had no impact in glioma cells where IDH was not mutated, suggesting this could one day be a viable therapy for patients.

Although AGI-5198 was a major breakthrough for targeting IDH mutations, cancer cells are clever and capable of adapting to resist therapies. At the biological level, that means when one isoform of IDH is targeted with a drug, the tumor may acquire resistance by developing a mutation in the other version of the protein (“isotype switching”), ultimately leading to disease recurrence. For example, a case report described two patients whose initial cancer had IDH1 R132 mutations, but developed an IDH2 mutation after the IDH1 mutation was treated.⁴ 

Along with isotype switching, developing a drug targeting mutant IDH in gliomas would present another challenge due to the unique anatomy of the brain. The blood-brain barrier is a semi-permeable specialized membrane designed to keep the bad stuff (think toxins) out of the brain while still allowing good things in (Fig. 2). Although the blood-brain barrier is critical to our survival, it limits the ability of most drugs to actually reach brain tumors, rendering them ineffective for patients. This was the case for early IDH inhibitors, which were potent, but demonstrated a limited ability to cross the blood-brain barrier in mouse models of glioma. The ability to combat isotype switching and a chemical structure designed to cross the blood-brain barrier – that’s what an ideal IDH inhibitor would look like for brain tumors.

In 2020, an international group of researchers reported such a compound: AG-881, now known as vorasidenib. In their paper they describe how they improved upon the chemical structure of other well-described mutant IDH inhibitors in an iterative fashion, tweaking specific chemical groups until they found one that inhibited both mutant IDH isoforms and exhibited brain penetrance in rat models.⁵ 

Developing IDH-specific inhibitors: in the clinic 

With vorasidenib showing promise in preclinical models, the next step was to begin testing the compound’s efficacy in patients with low-grade gliomas. The initial test was confirming if vorasidenib could effectively cross the blood-brain barrier, reach the tumor in patients, and effectively inhibit the mutant IDH enzyme. To investigate this, scientists conducted a phase 1 clinical trial where eligible patients took vorasidenib for 4 weeks prior to surgical resection of the tumor. Then, they analyzed the tumor tissue taken from patients, showing that vorasidenib reduced the concentration of 2-HG in tumor tissue by 95%.⁶

The results from this and other promising clinical trials then prompted the large phase 3 INDIGO clinical trial. The INDIGO study’s goal was to determine whether a regimen of vorasidenib could extend the time it took for a patient’s tumor to recur (“progression-free survival”) when compared to a placebo. Importantly, all patients in the trial had confirmed hotspot mutations in their tumor, either in the IDH1 amino acid R132 or the IDH2 amino acid R172. The results were striking: patients who were taking vorasidenib had more than double the time of progression-free survival (27.7 months) when compared to those who didn’t receive vorasidenib (11.1 months).⁷ Just over a year after the results were published, vorasidenib was FDA-approved for grade 2 gliomas with a suspected IDH1 or IDH2 mutation. 

Conclusion

Vorasidenib is an example of the astounding progress that can be made in science. In just 15 years, a critical mutation was discovered and a drug was developed, tested, and approved by the FDA, allowing it to make a difference for those living with brain tumors. Time will tell if vorasidenib also improves overall survival, but until then, this remarkable achievement reflects the dedication and collaboration of researchers committed to advancing treatment options for those with brain cancer.

Header Image Source: https://www.behance.net/gallery/19717365/Concept-for-Neurology-Congress#

Figure 1: Created by Author

Figure 2 Source: https://www.flickr.com/photos/nihgov/25209610730

Edited by Karli Norville

References

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