Dramatic In Vivo Efficacy of the EZH2-Inhibitor Tazemetostat in PBRM1-Mutated Human Chordoma Xenograft

Abstract

Chordomas are rare neoplasms characterized by a high recurrence rate and a poor long-term prognosis. Considering their chemo-/radio-resistance, alternative treatment strategies are strongly required, but their development is limited by the paucity of relevant preclinical models. Mutations affecting genes of the SWI/SNF complexes are frequently found in chordomas, suggesting a potential therapeutic effect of epigenetic regulators in this pathology. Twelve PDX models were established and characterized on histological and biomolecular features. Patients whose tumors were able to grow into mice had a statistically significant lower progression-free survival than those whose tumors did not grow after in vivo transplantation (<i>p</i> = 0.007). All PDXs maintained the same histopathological features as patients' tumors. Homozygous deletions of <i>CDKN2A/2B</i> (58.3%) and <i>PBRM1</i> (25%) variants were the most common genomic alterations found. In the tazemetostat treated PDX model harboring a <i>PBRM1</i> variant, an overall survival of 100% was observed. Our panel of chordoma PDXs represents a useful preclinical tool for both pharmacologic and biological assessments. The first demonstration of a high antitumor activity of tazemetostat in a PDX model harboring a <i>PBRM1</i> variant supports further evaluation for EZH2-inhibitors in this subgroup of chordomas.