Apr 19

The Snippet: Targeting metabolism in Renal Cell Carcinoma

Loss of VHL and elevated expression of HIF transcription factors leads to reprogramming of tumour cell metabolism, enabling renal cell carcinoma (RCC) cells to use carbons from glutamine-derived aspartate to drive pyrimidine biosynthesis. Now, researchers show that inhibition of glutamine availability decreases aspartate availability, leading to growth inhibition of RCC cells. Moreover, glutaminase 1 (GLS1) inhibition increases oxidative stress, leading to DNA replication stress and growth arrest. “These findings led us to combine a GLS1 inhibitor with an inhibitor of DNA repair enzymes — in this case, a poly(ADPribose) polymerase (PARP) inhibitor — to achieve therapeutic synergism,” explains Othon Iliopoulos. “In other words, we discovered how targeting a metabolic pathway renders VHL-deficient cancer cells sensitive to DNA repair mechanisms.” Iliopoulos hopes to take their findings directly to a clinical trial. “We now plan to treat patients with renal and other HIF-expressing cancers with this novel combination of GLS1 and PARP inhibitors,” he explains.

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