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. 2022 Mar 14;14(6):1486.
doi: 10.3390/cancers14061486.

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

Affiliations

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

Thibault Passeri et al. Cancers (Basel). .

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 (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.

Keywords: EZH2 inhibitor; chordoma; next-generation sequencing; patient-derived xenografts; targeted therapy.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Prognostic value of the in vivo tumor take on the progression-free survival (PFS) of corresponding chordoma patients (univariate analysis). The PFS was significantly lower for patients whose tumors were able to grow into nude mice compared to patients whose tumors did not grow after in vivo transplantation (Wilcoxon test, p = 0.007).
Figure 2
Figure 2
Histological and immunohistochemical comparison between primary patients’ tumors and their corresponding xenografts (CD3, CD7, CD39 and CD45 models). Histological analyses with HES showed that xenografts resembled the primary tumors from which they derived. All primary patients’ tumors and their corresponding xenografts were immunolabeled with brachyury (magnification ×400).
Figure 3
Figure 3
Percentage of H3K27me3 positive cells according to PBRM1-mutated status in the 12 PDX chordoma models. A significantly higher expression of H3K27me3 in the PBRM1-mutated compared to non-PBRM1-mutated PDX models was noted. * achieve statistical significance compared to control (p < 0.05) by Mann–Whitney test.
Figure 4
Figure 4
In vivo efficacy of tazemetostat in the CD39 chordoma PDX and pharmacodynamics study. PDX tumor-bearing mice were randomized into each treatment group (n = 5 per group) and treated with tazemetostat 75 mg/kg twice a day, 5 days per week (green). Untreated control is shown in black. (A) Relative tumor volume. Tumor growth was evaluated by plotting the mean of the relative tumor volume ± SD per group. (B) Probability of tumor progression. The time to reach RTV x 2 for each treated mouse was calculated. (C) Results for the FACS analysis in neutrophils. A clear shift of the H3K27me3 staining in the treated group compared to the control was observed (** achieve statistical significance compared to control (p = 0.005) by Mann–Whitney test). (D) Immunohistochemical (IHC) staining results for H3K27me3 in treated mice with anti-EZH2 drug (tazemetostat) and control mice. A decreased expression of H3K27me3 was noted in the treatment group in comparison with the control group (magnification ×20).
Figure 5
Figure 5
Inter-relationship between PRC2 and SWI/SNF complexes. The SWI/SNF complex is composed of 9 to 12 proteins and characterized by an ATPase function via 2 proteins, SMARCA2 (BRM) and SMARCA4 (BRG) which drives nucleosome remodeling. This complex is formed by a constant protein core and also some optional proteins distinguishing 2 types: BAF (BRG1-associated factors) and PBAF (Polychromo-BRG1-associated factors) complexes. (A) In basal situation, SWI/SNF complexes block the PRC2 complex epigenetic silencing of Polycomb targets; in this basal situation, EZH2 acts as the catalytic subunit of the PRC2 Polycomb repressor complex and catalyzes the trimethylation of histone 3 lysine 27 (H3K27me3) at the promoters of target genes. (B) Perturbations in SWI/SNF activity, such as the loss of the specific subunit PBRM1 (BAF180), lead to oncogenesis via imbalanced PRC2 activity and aberrant epigenetic silencing of Polycomb targets. (C) The EZH2-inhibor re-establishes the balance between the complexes by inhibition of EZH2 methyltransferase activity.

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