Critical Genes Associated with Glioblastoma (GBM): IDH-1/2

Research has shown that many genetic factors influence glioblastoma (GBM) formation and progression are influenced by numerous genetic factors, as studies have demonstrated. One of these genes is Isocitrate DeHydrogenase (IDH) . This article briefly discusses IDH functions and its place in GBM treatment.

What Is IDH 1/2?

IDH 1 and 2 are metabolic enzymes encoded by the IDH 1 and 2 genes. They have many cellular functions, one of the most important being their role in energy production through the Krebs cycle. This cycle is an important chemical process allowing living cells to obtain energy from nutrients.

Genetic studies found IDH1/2 genes in %70-80 of low-grade gliomas and a large proportion of secondary glioblastomas. These data added a new dimension to GBM classification, dividing it into IDH-mutant GBM, usually representing secondary GBM, and IDH-nonmutant GBM, including primary GBM.

What Are the Cellular Effects of IDH 1/2 Mutations?

Alpha-ketoglutarate (α-KG) is a compound produced during energy generation in the Krebs cycle. Mutation alters IDH1/2 enzyme function, causing KG to convert into another intermediate, alpha-hydroxyglutaric acid (2-HG). Accumulation of 2-HG in the body disrupts enzymes important for cellular cycles, altering cellular metabolism and epigenetic regulation, and DNA repair mechanisms are blocked, contributing to tumor formation. It also inhibits demethylases that remove methyl groups from histones and DNA, disrupting cellular differentiation. In addition, it accelerates new blood vessel formation , which contributes to tumor formation, and activates genes supporting cell survival in low-oxygen environments.

Which Tumors Have IDH 1/2 Mutations?

IDH1 and IDH2 mutations occur in many tumors, particularly grade 2 and 3 astrocytomas, oligodendrogliomas, oligoastrocytomas, secondary glioblastomas, chondrosarcomas, angioimmunoblastic T-cell lymphomas, intrahepatic cholangiocarcinomas, acute myeloid leukemias, skin cancers, myelodysplastic syndromes, myeloproliferative neoplasms, and colon and lung cancers.

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Which IDH Inhibitors Have US Food and Drug Administration (FDA) Approval?

The IDH1-blocking agent approved for acute myeloid leukemia, ivosidenib (Tibsovo) and the IDH2 blocker, enasidenib , are used. Both primarily target the mutation-induced increase in 2-HG, reversing it to normal levels. Research found the most frequent adverse effects after Tibsovo use were fatigue, joint pain, irregular heartbeat, diarrhea, shortness of breath, cough, and constipation. Adverse effects following enasidenib included nausea, vomiting, diarrhea, and decreased appetite.

Have IDH Inhibitors Been Tested in GBM? What Are the Results?

IDH mutations are thought to trigger tumor formation because they commonly occur in secondary glioblastomas. IDH inhibitors have therefore begun to be studied for GBM patients.

In Japan, DS-1001b, an IDH1 inhibitor capable of crossing the blood–brain barrier to reach its target, underwent a phase 1 clinical trial . After treatment, among 9 patients, 2 showed small responses toward improvement, while the remainder had stable progression. Another study found that among 29 patients, one had a complete response while the others did not respond.

In another New York-based study, brain tumor surgery removed as much tumor as possible, and patients subsequently receiving IDH inhibitors had lower 2-HG levels. The same team stated that low 2-HG levels in patients receiving chemotherapy and radiotherapy improved quality of life .

Other research has noted that an IDH mutation provides patients with a better prognosis , predicting disease outcome, so silencing the enzyme with inhibitors may make the tumor more aggressive. A new inhibitory approach therefore targeted the DNA repair protein Poly (ADP-Ribose) Polymerase (PARP). Mutations in IDH enzymes increased glioma cells' susceptibility to PARP inhibition. Because the blood–brain barrier prevents PARP inhibitors from reaching their target, GBM studies progress less quickly than studies in other cancers. However, experiments show PARP inhibitors sensitize GBM patients to radiotherapy.