Metabolic vulnerabilities in IDH1/2‐mutated solid tumours lead to phase IB/II clinical trial using metformin and chloroquine
Authors: Khurshed Mohammed , Molenaar Remco J , van Noorden Cornelis , Wilmink Johanna W 
Published: June 2021

IntroductionHotspot mutations in the genes IDH1 and IDH2 (isocitrate dehydrogenase 1 and 2) occur in 60% of chondrosarcoma, 80% of WHO grade II–IV glioma and 20% of intrahepatic cholangiocarcinoma. Mutations induce a neoenzymatic activity that leads to the production and accumulation of D‐2‐hydroxyglutarate (D‐2HG). This causes metabolic rewiring and stress that is not fully understood. We previously postulated that the tricarboxylic acid (TCA) cycle, rather than glycolytic lactate production, is the predominant metabolic pathway in IDH1MUT glioma.ResultsTo confirm this hypothesis in a clinical setting, we used a novel technique of quantitative targeted next‐generation sequencing of 104 metabolic enzymes, on a cohort of 66 clinical gliomas. We confirmed the predominance of the oxidative metabolism in IDH1MUT gliomas, which is driven by lactate and glutamate anaplerosis. Preferential glutamate processing in IDH1MUT gliomas was confirmed by in situ enzyme activity mapping experiments in clinical gliomas of known IDH status, indicating that IDH1MUT gliomas depend on glutamatolysis, rather than glutaminolysis. We aim to specifically inhibit the metabolic processes that are essential to IDHMUT tumours using the oral antidiabetic metformin and the oral antimalarial drug chloroquine, which specifically target the metabolic vulnerabilities that are caused by IDHMUT.Clinical trialWe started a dose‐finding phase Ib/II clinical trial, in which patients with IDHMUT chondrosarcoma, glioma and intrahepatic cholangiocarcinoma are treated with a combination of metformin and chloroquine. The primary objective is to determine the maximum tolerated dose to establish the recommended dose for a phase II clinical trial. Secondary objectives of the study include (1) determination of pharmacokinetics and toxic effects of the study therapy, (2) investigation of tumour responses to metformin plus chloroquine in IDHMUT cancers using CT/MRI scans; and (3) whether tumour responses can be measured by noninvasive D‐2HG measurements (mass spectrometry and magnetic resonance spectroscopy) of tumour tissue, serum, urine, and/or bile or next‐generation sequencing of circulating tumour DNA (liquid biopsies). This study may open a novel treatment avenue for IDHMUT high‐grade chondrosarcoma, glioma and intrahepatic cholangiocarcinoma by repurposing the combination of two inexpensive drugs that are already approved for other indications.Support or Funding InformationThis work was supported by Dutch Cancer Society Grants KWF‐UVA 2014‐6839 (to M.K., R.J.M., and C.J.F.V.N.) and AMC2016.1‐10460 (to M.K., R.J.M., J.W.W., and C.J.F.V.N.).
A) Targeted RNAseq of clinical glioma samples. Gene expression levels of genes involved in glycolysis, glutaminolysis and the TCA cycle. B) Metabolic mapping of glutamate dehydrogenase (GLUD) and glutaminase (GLS). Cryostat sections and (C) quantification activity levels in IDH1WT (n=5) and IDH1MUT (n=7)imageA) Targeted RNAseq of clinical glioma samples. Gene expression levels of genes involved in glycolysis, glutaminolysis and the TCA cycle. B) Metabolic mapping of glutamate dehydrogenase (GLUD) and glutaminase (GLS). Cryostat sections and (C) quantification activity levels in IDH1WT (n=5) and IDH1MUT (n=7)
D) Cellular carbohydrate and glutamine metabolism showing the pathways in which IDH1 and IDH2 are functional. The conversion of glutamine into α‐ketoglutarate occurs in the glutaminolysis pathway and the last step is catalysed by glutamate dehydrogenase (GLUD), which is inhibited by chloroquine and metformin. Complex I of the electron transport chain (ETC) is also inhibited by metformin. E) Dosing schedule and study design for patients. MRS, magnetic resonance spectroscopy; MS, mass spectrometryimageD) Cellular carbohydrate and glutamine metabolism showing the pathways in which IDH1 and IDH2 are functional. The conversion of glutamine into α‐ketoglutarate occurs in the glutaminolysis pathway and the last step is catalysed by glutamate dehydrogenase (GLUD), which is inhibited by chloroquine and metformin. Complex I of the electron transport chain (ETC) is also inhibited by metformin. E) Dosing schedule and study design for patients. MRS, magnetic resonance spectroscopy; MS, mass spectrometryThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.