Efficacy and mechanistic basis for epigenetic therapies in osteosarcoma

Epigenetic deregulation is an emerging hallmark of cancer that enables tumor cells to escape surveillance by tumor suppressors and ultimately progress.  The structure of the epigenome consists of covalent modifications of chromatin components, including acetylation by histone acetyltransferases (HATs) and deacetylation by histone deacetylases (HDACs).  Targeting these enzymes with inhibitors to restore epigenetic homeostasis has been explored for many cancers (Figure 1).  Osteosarcoma, an aggressive bone malignancy that primarily affects children and young adults, is notable for widespread genetic and epigenetic instability.  For example, recent whole-genome sequencing suggests that osteosarcomas are driven by a relatively small number of mutations compared to adult tumors – frequently in genes encoding epigenetic regulators – while copy number alterations and structural variants predominate.  Epigenetics may also be critical in osteosarcoma metastases, which are accompanied by a shift in the cancer epigenome despite minor changes in the mutational landscape.  For these reasons, the emergence of epigenomic therapies has been met with great enthusiasm by those studying osteosarcoma, owing to the relatively limited activity of other newer agents and the significant epigenetic dysregulation observed in osteosarcoma tumors. 

In collaboration with the laboratory of Dr. Ed Greenfield at the Indiana University School of Medicine, we recently developed a three-dimensional in vitro osteosarcoma drug-screening platform that provides highly-uniform sarcospheres to mimic micrometastatic disease.  Sarcospheres generated from three highly-metastatic human cell lines were then used to screen the NCI panel of 114 FDA-approved oncology drugs (Figure 2).  Two of the fifteen most effective drugs were the HDAC inhibitors romidepsin and vorinostat, which were the only two epigenetic therapies included in the panel.  After further characterization in normal cell lines and in combination with standard-of-care MAP (methotrexate, doxorubicin, and cisplatin) chemotherapy, romidepsin emerged as the most promising drug evaluated.  These findings are consistent with the growing interest in epigenetic therapies for the treatment of osteosarcoma and suggest the need for further preclinical evaluation of the agents to optimize their success in scarcely available clinical trials.