Abstract
Targeted therapies have revolutionized cancer treatment. It is well established that alterations of chromatin configuration and modifications affect tumorigenesis of some, possibly most, bone and soft-tissue sarcomas. As epigenetic regulators play a major role in the development of bone and soft-tissue sarcomas, epigenetic drugs provide a novel potential avenue for rational targeted therapies for these aggressive cancers. The present review summarizes the application of epigenetic drugs for clinical utilization in bone and soft-tissue sarcomas and provides an overview of clinical trials currently evaluating epigenetic therapies in this space.
Highlights
Bone and soft-tissue sarcomas have been treated with combinations of surgery, chemotherapy, and radiation
Alterations of chromatin configuration and associated epigenetic modifiers have been implicated in the tumorigenesis of bone and soft-tissue sarcomas, and these results open the possibility of novel drugs targeting epigenetic modifications in this patient population [4,5,6,7,8]. e present review aims to provide an overview of the preclinical development of epigenetic-related targeted drugs and their respective clinical applications in bone and soft-tissue sarcomas
The cytidine analogues 5-Azacytidine/VIDAZA (AZA) and 5-Aza-2′-deoxycytidine/DACOGEN (DAC or decitabine) have been shown to induce hypomethylation in cancer cells, but have mostly been used in the context of hematologic malignancies. e next-generation DNA methyltransferase inhibitor (DNMTi) SGI-110 is a new small-molecule DNMTi agent whose resistance to cytidine deaminase has resulted in a longer half-life in an aqueous solution compared to firstgeneration DNMTis. e gradual cleavage of guadecitabine into decitabine leads to more prolonged and stable release of the drug, as opposed to decitabine’s short-term peak in plasma concentration
Summary
Bone and soft-tissue sarcomas have been treated with combinations of surgery, chemotherapy, and radiation. 40% of patients with soft-tissue sarcoma develop metastases, and outcomes for patients with metastatic disease remain poor [1, 2]. Alterations of chromatin configuration and associated epigenetic modifiers have been implicated in the tumorigenesis of bone and soft-tissue sarcomas, and these results open the possibility of novel drugs targeting epigenetic modifications in this patient population [4,5,6,7,8]. E present review aims to provide an overview of the preclinical development of epigenetic-related targeted drugs and their respective clinical applications in bone and soft-tissue sarcomas. We analyze therapeutic targets involving each layer of epigenetic control, including at the level of DNA, histone, enzymatic complexes, and chromatin. We highlight clinical trials investigating the use of epigenetic therapeutics in bone and soft-tissue sarcomas (Table 1)
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