IDH inhibitors represent a modern advancement in cancer treatment, offering a targeted approach. These medications specifically aim to counteract the effects of certain genetic changes found in cancer cells. Unlike traditional chemotherapy, which broadly affects dividing cells, IDH inhibitors provide a more precise way to manage certain cancers by focusing on these molecular abnormalities.
The Role of IDH Mutations in Cancer
The isocitrate dehydrogenase (IDH) enzyme normally helps convert isocitrate into alpha-ketoglutarate (α-KG) for cellular energy. However, mutations in the IDH1 or IDH2 genes alter the enzyme’s function, causing it to produce an abnormal substance called 2-hydroxyglutarate (2-HG). This mutated enzyme gains a new function, converting α-KG into 2-HG, which then accumulates in cancer cells.
The buildup of 2-HG disrupts normal cellular processes by interfering with enzymes that regulate DNA and histone modifications. This leads to widespread changes in gene expression, promoting tumor growth and survival. Specifically, 2-HG can lead to increased DNA methylation and silencing of tumor suppressor genes, further contributing to cancer development. 2-HG also influences cancer cell metabolism, aiding their survival and growth, and can affect the immune environment around tumors, hindering the body’s ability to fight cancer.
How IDH Inhibitors Work
IDH inhibitors are small molecules designed to specifically block the activity of the mutated IDH enzyme, reducing the production of the harmful oncometabolite 2-HG. By lowering 2-HG levels, IDH inhibitors help restore normal cellular functions and reverse some epigenetic changes caused by the mutation.
The reduction in 2-HG levels helps restore a more normal epigenetic landscape by reversing the DNA methylation and reactivating silenced tumor suppressor genes. This action helps reverse the cellular changes that drive cancer growth and can promote cellular differentiation, particularly in acute myeloid leukemia where cancer cells often fail to mature properly.
Conditions Treated with IDH Inhibitors
IDH inhibitors are approved or under investigation for specific cancers with IDH mutations. These include acute myeloid leukemia (AML), cholangiocarcinoma (bile duct cancer), and certain types of glioma (brain tumors). IDH mutations are found in approximately 10-20% of AML cases, a significant proportion (often 70-80%) of lower-grade gliomas, and about 10-20% of cholangiocarcinomas.
Treatment with IDH inhibitors is highly specific, requiring genetic or biomarker testing to identify patients whose cancer cells have the relevant IDH1 or IDH2 mutations. Approved IDH inhibitors include ivosidenib (Tibsovo) for mutant IDH1 and enasidenib (Idhifa) for mutant IDH2, both used in AML. Vorasidenib (Voranigo), an IDH1 inhibitor, has been approved for grade 2 IDH-mutant gliomas. Ongoing clinical trials are also evaluating these and other IDH inhibitors for various IDH-mutated solid tumors, including cholangiocarcinoma.
Practical Considerations for Patients
IDH inhibitors are typically taken orally, often daily, offering a convenient administration method. Patients may experience side effects, such as nausea and fatigue. It is important to discuss any side effects with their healthcare team.
A specific, potentially serious side effect is differentiation syndrome (DS), observed in patients with IDH-mutated AML. Symptoms include fever, shortness of breath, rapid weight gain, peripheral edema, and pulmonary infiltrates. DS can occur from 10 days to 5 months after starting treatment. Early recognition and prompt management, often with corticosteroids, are important to mitigate severe outcomes. Patients should maintain open communication with their healthcare provider to discuss treatment options and any concerns.