Combinatorial strategies to potentiate the efficacy of HDAC inhibitors in fusion-positive sarcomas

Fusion positive (FP) sarcomas are characterized by chromosomal rearrangements generating pathognomonic fusion transcripts and oncoproteins. In Ewing's sarcoma family of tumors (ESFTs), FP-rhabdomyosarcomas (FP-RMS) and synovial sarcomas (SS), the most common and aggressive forms of sarcomas in childhood and adolescence, the oncogenic rearrangements involve transcription cofactors causing widespread epigenetic rewiring and aberrant gene expression. Through the cooperation with histone deacetylases (HDACs) in transcription regulatory complexes, the fusion oncoproteins affect histone acetylation and chromatin remodeling. The participation of HDACs in core mechanisms of sarcoma cell transformation has paved the way to the investigation of HDAC inhibitors (HDACis) for therapeutic intervention. Preclinical studies have provided convincing evidence that HDAC activity abrogation can revert malignant cell features driven by FET-ETS, PAX3/7-FOXO1 or SS18-SSX fusion oncogenes in ESFTs, FP-RMS, or SS models, respectively, resulting in in vitro and in vivo growth inhibition. While clinical trials of HDACi monotherapies led to drug approval in some hematologic malignancies, no significant therapeutic benefit has been reported in solid tumors, including sarcomas. HDACi-based combination therapies with targeted or conventional anticancer agents have shown limited efficacy in early studies recruiting sarcoma patients, although partial responses and disease stabilization have been reported. In these trials, sarcomas were represented, however, as unclassified group in most cases. We summarize, here, studies addressing the role of HDACs in FP-sarcoma pathobiology and HDACi-based rational drug combinations. Finally, we discuss the opportunity of exploiting drug inhibitory profile and expression/function of specific HDAC isoenzymes to harness the full therapeutic potential of HDACis in these sarcoma histotypes.