Abstract
Simple SummaryChordomas are rare bone tumors characterized by a high recurrence rate. Presently, no medical treatment is available for advanced diseases due to the lack of molecular data and preclinical models. The current study showed the establishment and characterization of the largest panel chordoma xenografts, allowing pharmacological studies. In one PBRM1-mutated model, we demonstrated a strong therapeutic efficacy of the EZH2-inhibitor tazemetostat, encouraging further research on EZH2-inhibitors in chordomas.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.
Highlights
Chordomas are rare bone neoplasms derived from notochordal cell rests
We observed a slow growth of all new models, corresponding to the natural tumor’s speed observed in the clinics
By establishing and deeply characterizing several chordoma xenograft obtained from primary tumors (PDX) models from different patients with various clinical features, locations, immunohistochemically and genomic variations, we contribute to a growing arsenal of relevant therapeutic tools in the management of chordomas
Summary
Chordomas are rare bone neoplasms derived from notochordal cell rests. Their origin explains their most common location in the midline neuraxis [1]. They are considered to be slow growing; recurrence rates are high, and the long-term prognosis remains poor. The mainstay therapeutic strategy consists of a maximal surgical resection followed by a high-dose proton therapy [3,4]. Considering their close relationship with eloquent neurological structures, maximal resection could be difficult to achieve, which is especially problematic given the chemoradiotherapy resistance of chordomas [5]. Alternative treatment strategies are strongly required because of the restricted efficacy of surgery and/or reirradiation in the relapse tumor [3]
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