Mesenchymal chondrosarcoma (MCS) is an aggressive subtype of chondrosarcoma, mainly affecting children and young adults. Before the discovery of a recurrent HEY1-NCoA2 gene fusion in most MCS patient samples, MCS diagnosis presented a challenge due to histopathological similarities to many other small blue round cell neoplasms of primitive sarcomas. With current treatments, the median event-free survival is 57 months. MCS characteristics are high extraskeletal occurrence and a late recurrence rate. Surgical resection shows improved survival rates compared to treatment with conventional chemotherapy.
This study identified a potential therapeutic agent to treat HEY-NCoA2 gene fusion-driven mesenchymal chondrosarcoma (MCS), which is already available in the clinic, imatinib mesylate. Our findings highlighted the potential of combining biological and genome-wide functional association network frameworks to facilitate the identification of proxy druggable targets of MCS since HEY1-NCoA2 gene fusion cannot yet be directly targeted. Therefore we show the rationale to utilize the repurposing of licensed drugs strategy for the treatment of MCS and the workflow of this study could be applied to other rare single fusion-driven tumors. This strategy also supports current efforts for reinvigorating therapy development in underresearched rare cancers, without preclinical models and in which de novo drug development is, in the majority of cases, impractical. Additionally, it can also identify the potential resistance of these tumors to currently used chemotherapy to treat them. Lastly, this work rationally justifies a re-evaluation of licensed multikinase inhibitor imatinib to treat HEY1-NCoA2 fusion-driven MCS in a clinical trial.
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