A/Prof Daniel Thomas

Lipid levels may play a key role in the growth of cancer cells that have IDH1 gene mutations such as in acute myeloid leukaemia, researchers from South Australia have found.

The findings suggest that a low fat diet or lipid-lowering medications may be potential interventions to reduce progression of some cancers, according to researchers at the South Australian Health and Medical Research Institute (SAHMRI).

In a paper published in Cancer Discovery (link here) they show that IDH1 gene mutations are associated with altered fatty acid metabolism that means cells cannot synthesise their own lipids and must obtain it from the diet.

IDH1 mutations are found in many cancers including AML, myelodysplastic syndromes (MDS), glioma, T-cell acute lymphoblastic leukaemia (ALL), chondrosarcoma, and cholangiocarcinoma.

The international collaboration showed the mutation is characterised by impaired de novo lipid synthesis caused by a combination of enhanced β-oxidation, depletion of NADPH, and defective reductive carboxylation. the defect was not rescued by the mIDH1- specific inhibitor ivosidenib, currently used in AML treatment.

The researchers then showed that a lipid-free diet resulted in growth inhibition of primary acute myeloid leukaemia (AML) blasts, suggesting that this mutation may be a targetable vulnerability for several types of cancer.

“We replicated the results in a range of cancer types, comparing a regular diet with one that was completely fat-free and were surprised to find tumours with IDH1 were stopped in their tracks when starved of lipids,” said lead investigator Dr Daniel Thomas (PhD).

“Unlike other tumours, cancers with IDH1 mutations are addicted to lipids, they need to eat them and they need to make them from scratch,” said Dr Thomas, Associate Professor, Haematology Myeloid Metabolism Group (Precision Cancer Medicine) at SAHMRI.

In the paper, co-authored with scientists from Adelaide University and Stanford University in the US, the researchers explained that the metabolic enzymes isocitrate dehydrogenase 1 and 2 (IDH) are mutated in multiple cancers and drive production of (R)-2-hydroxyglutarate (2HG).

The team identified a lipid synthesis enzyme, acetyl CoA carboxylase 1 (ACC1), as a synthetic lethal target in mutant IDH1, but not mutant IDH2, cancers.

When they analysed the metabolome of primary AML blasts, the researchers identified a mutant IDH1-specific reduction in fatty acids. The mutation also induced a switch to b-oxidation indicating reprogramming of metabolism toward a reliance on fatty acids.

Leukaemia cells with the IDH1 mutation showed depletion of NADPH with defective reductive carboxylation.

Further work using human xenograft models showed that a lipid-free diet markedly slowed the growth of mutant IDH1 AML, but not healthy CD34+ hematopoietic stem/progenitor cells or [mutant IDH2] AML.

“Genetic and pharmacologic targeting of ACC1 resulted in the growth inhibition of mIDH1 cancers not reversible by ivosidenib. Critically, the pharmacologic targeting of ACC1 improved the sensitivity of mIDH1 AML to venetoclax,” they wrote.

“These results have implications for dietary and therapeutic approaches for patients with mIDH1 cancers,” the researchers concluded.

“More work needs to be done to substantiate our findings in humans long term, but for anyone with an IDH1 mutant cancer …  our research suggests erring on the side of caution by avoiding foods that are high in saturated fats,” Dr Thomas said.