Combination of approaches slowed osteosarcoma growth in preclinical models — News-Medical

Scientists, whose work was co-led by specialists at St. Jude Children's Research Hospital, identified a potential therapeutic vulnerability in certain forms of osteosarcoma, a pediatric bone cancer. Combining approaches aimed at degrading the EP300 protein and inhibiting AKT slowed tumor growth and prolonged survival in preclinical models, News-Medical reports.

Link to AKT mutations

The study results were published in the Journal of Experimental Medicine. Scientists tested whether EP300 degradation could be effective against osteosarcoma, as this approach had previously shown an effect in neuroblastoma models. A small but significant proportion of osteosarcoma samples proved particularly sensitive to degradation of this protein.

Analysis of the tumors' genetic features showed that most samples sensitive to EP300 degradation had mutations that excessively activated the AKT signaling pathway. AKT regulates a number of cellular processes and is often disrupted in cancer. Inhibitors approved by the U.S. Food and Drug Administration already exist to suppress AKT.

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Results in mouse models

Combining EP300 degradation with AKT inhibition demonstrated a synergistic effect in patient-derived tumor xenografts in mice: tumors grew more slowly, and the animals' survival increased. The authors suggest that mutations associated with AKT hyperactivation could become a biomarker of sensitivity to this approach.

A biochemical comparison of sensitive and resistant tumors also showed that sensitive tumors had a lower rate of overall protein synthesis. According to the researchers, resistant osteosarcomas may counteract EP300 degradation by producing more proteins than the cell can destroy. In the future, genomic sequencing may help identify patients whose tumors could potentially be sensitive to this combination.