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Oncology - New Targets in Cancer
Novel Metabolic Therapies for Blood and Brain Cancer
The genes encoding isocitrate dehydrogenase 1 and 2 (IDH1/2) are mutated in brain cancer and leukaemia and drive the production of the oncometabolite (R)-2-hydroxyglutarate (R-2HG). However, specific differences between these two mutations with targetable implications have not been described. Dr Dan Thomas is a clinician and researcher who runs the Myeloid Metabolism Laboratory at SAHMRI. His team has recently discovered a novel susceptibility specifically for IDH1 mutation (mIDH1) by identifying the lipid synthesis enzyme ACC1 (acetyl CoA carboxylase 1) as a synthetic lethal target, published recently in Cancer Discovery and highlighted as one of the most important papers for 2023 by the European Cancer Association. By analyzing the metabolome of primary patient cells, his team identified a mIDH1-specific reduction in fatty acids compared to healthy progenitor cells that was not observed in IDH2-mutant cancer. Moreover, mIDH1 cells exhibited an increase in acyl-carnitine linked fatty acids destined for the mitochondria, indicating a switch to beta-oxidation. Overall, their data show that mIDH1 cancer cells have a higher dependency on both exogenous and de novo fatty acids than mIDH2 cancers.
This suggests that differences in intracellular localisation between cytoplasmic IDH1 and mitochondrial IDH2 can have profound effects on metabolic phenotypes. These insights are important because it demonstrates novel targets for IDH1 mutant cancers beyond the production of the oncometabolite (R)-2-hydroxyglutarate, and offers hope for designing an ultra-precision approach encompassing diet and targeted therapy for cancer patients with IDH1, but not IDH2, mutant cancers. This is clinically relevant because emerging results from clinical trials testing mutant IDH inhibitors, such as ivosidenib, do not always result in tumour regression despite marked decreases in the oncometabolite. Dan's research suggests other metabolic dependencies beyond the Warburg effect, depending on somatic mutation context, such as mitochondrial-driven beta oxidation are also involved in cancer metabolism. This paper reinforces other recent studies supporting the notion that many cancers are not dependent on ATP or carbon supply for growth but are desperate for an adequate supply of re-usable NADPH (via NADH) and are prepared to sacrifice both de novo and exogenous fatty acids to guarantee this.
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