The Histone Deacetylase Inhibitor Entinostat/Syndax 275 in Osteosarcoma

The prognosis for metastatic osteosarcoma (OS) is poor and has not changed in several decades. Therapeutic paradigms that target and exploit novel molecular pathways are desperately needed. Recent preclinical data suggests that modulation of the Fas/FasL pathway may offer benefit in the treatment of refractory osteosarcoma. Fas and FasL are complimentary receptor-ligand proteins. Fas is expressed in multiple tissues, whereas FasL is restricted to privilege organs, such as the lung. Fas expression has been shown to inversely correlate with the metastatic potential of OS cells; tumor cells which express high levels of Fas have decreased metastatic potential and the ones that reach the lung undergo cell death upon interaction with constitutive FasL in the lung. Agents such as gemcitabine and the HDAC inhibitor, entinostat/Syndax 275, have been shown to upregulate Fas expression on OS cells, potentially leading to decreased OS pulmonary metastasis and improved outcome. Clinical trials are in development to evaluate this combination as a potential treatment option for patients with refractory OS.