BioProject

The heterogenous genomic nature of most sarcoma subtypes makes them especially indicated for personalized treatment approaches. More...

The heterogenous genomic nature of most sarcoma subtypes makes them especially indicated for personalized treatment approaches. Here, we developed a personalized medicine strategy based in the use of patient-derived cell lines as a drug-testing platform. Targeted sequencing of a panel of cancer-related genes in these models revealed the presence of IDH1 and IDH2 mutations in two chondrosarcomas. Mutant IDH (mIDH) enzymes produce the oncometabolite 2-HG which contributes to driving tumor growth. Thus, we treated several chondrosarcoma models with specific mIDH1/2 inhibitors. Among these treatments, only the mIDH2 inhibitor enasidenib was able to decrease 2-HG levels and to efficiently reduce the viability of mIDH2 chondrosarcoma cells. Importantly, oral administration of enasidenib in xenografted mice resulted in a complete abrogation of tumor growth. Enasidenib induced a profound remodeling of the transcriptomic landscape not associated to changes in the 5mC methylation levels and its anti-tumor effects were associated to the repression of proliferative pathways such as those controlled by E2F factors. Overall, this work provides the first preclinical evidence for the use of enasidenib to treat mIDH2 chondrosarcomas. Overall design: To investigate the effect of enasidenib in the methylation, we treated IDH2 mutated chondrosarcoma primary cell line for 48 h with the inhibitor (20 μM) and with the vehicle DMSO (control). The EZ-96 DNA Methylation Kit (Zymo Research) was used to perform the bisulphite conversion. The processed DNA samples were then hybridised to Infinium MethylationEPIC BeadChips following the Illumina Infinium HD Methylation Assay protocol. Less...