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 (p = 0.007). All PDXs maintained the same histopathological features as patients'
tumors. Homozygous deletions of CDKN2A/2B (58.3%) and PBRM1 (25%) variants were the most common genomic alterations found. In the
tazemetostat treated PDX model harboring a PBRM1 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 PBRM1 variant supports further evaluation for EZH2-inhibitors in this subgroup of
chordomas.