IDH mutations in cancer and progress toward development of targeted therapeutics

Abstract

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes, converting isocitrate to α-ketoglutarate (αKG).IDH1 and IDH2 mutations have been identified in multiple tumor types, including gliomas and myeloid malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Here we provide an overview of the function of normal and mutated IDH, discuss the role of IDH mutations in tumorigenesis and progression and review the key clinical considerations when treating IDH-mutated tumors based on emerging clinical data from mutant IDH1/2 inhibitor trials. IDH1 and IDH2 mutations confer neomorphic activity in the mutant protein, resulting in the conversion of αKG to the oncometabolite, D-2-hydroxyglutarate (2-HG). The subsequent accumulation of 2-HG results in epigenetic dysregulation via inhibition of αKG-dependent histone and DNA demethylases, and a block in cellular differentiation. There is growing preclinical and clinical evidence suggesting that IDHmutations are involved in neoplasia. Furthermore, preclinical studies assessing small molecule inhibitors of mutant IDH1/2 enzymes have provided proof of concept that this approach decreases intracellular 2-HG levels, reverses epigenetic dysregulation and induces cellular differentiation. Phase I studies of mutant IDH inhibitors are currently ongoing in patients with IDH-mutant hematologic and solid tumors, with early data in hematologic tumors suggesting a manageable safety profile as well as clinical benefit, with a mechanism of action based on differentiation of malignant cells. Inhibition of mutant IDH shows promise as a treatment approach in hematologic malignancies, with further development ongoing in solid tumors and glioma. The mutant IDH inhibitors may have clinical utility both as single agents and in combination strategies that target additional oncogenic pathways.

Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C

“…Glioblastoma, for example, while still diagnosed based on anatomy and histopathology (4), has been further separated into subtypes based on genetic alterations, expression signatures, and long-term survival (5,6). This approach identified a subset of patients with gain-offunction mutations in a gene that had not previously been linked to cancer, IDH1 (6), leading to the development of inhibitors that are being investigated in clinical trials (7).…”

Species specificity of an adrenal androgen-mediated kill-switch triggered by p53 inactivation

“…If the reason for hypersensitivity of canine CH to HD DHEA turns out to be that CH tumors have IDH mutations, then our data in canines may translate to a wide array of currently treatment-refractory human tumors known to have such mutations. 75 The p53 tumor suppressor is the most frequently mutated gene in human cancer, 76 and its experimental manipulation in laboratory mice has provided some of the bedrock theory behind both basic science and treatment models of human cancer. If a p53 back-up role for DHEA is proven, an unfortunate consequence would be that, since much of this bedrock theory of p53 function is based on animal models lacking circulating DHEAS, and therefore the appropriate evolutionary context for human comparison, much of it could be called into question.…”

Agonistic targeting of TLR1/TLR2 induces p38 MAPK-dependent apoptosis and NFκB-dependent differentiation of AML cells

“…13 Recent advances have been made to differentiate other AML subtypes, such as isocitrate dehydrogenase 1/2 mutated AML. [14][15][16] These findings suggest that differentiation-based therapies may reach clinical utility also in other subtypes of AML.…”

“…Five million human MA9 cells were treated with Pam3CSK4 for 3 days and then injected into sublethally irradiated (250 cGy) NOD scid g (NSG; The Jackson Laboratory) mice. Blood samplings of the NSG mice were performed 4 weeks posttransplantation, and the experiment was terminated 16 (for Kaplan-Meier curves only). Correlation between TLR1 and TLR2 mRNA expression was calculated using Spearman's rank correlation.…”