PhD Scientific Days 2024

Poster Session Q - Pathological and Oncological Sciences 2.

EZH2 is a prognostic biomarker and potential novel therapeutic target in anaplastic (grade 3) meningioma

Text of the abstract

Meningiomas are the most common central nervous system tumors in adults, with indolent (grade 1), more aggressive (atypical, grade 2) and clearly malignant (anaplastic, grade 3) types. Aggressive meningiomas show transcriptomic and epigenetic profiles being indicative for the activation of Polycoomb Repressive Complex 2 (PRC2), an important epigenetic regulator. The catalytic subunit of PRC2 is the Enhancer of Zeste Homologue 2 (EZH2).
Our aim was to determine the prognostic value of EZH2 expression in meningiomas, particularly in the grade 3 type and the effect of EZH2 inhibition in the human grade 3 meningioma cell line IOMM-Lee both in vitro and in vivo.
Firstly, we examined EZH2 expression in meningioma (grade 1-3) tissue samples (n=13-17/group) by immunohistochemistry (IHC). Immunopositivity was assessed digitally and the results were compared by the H-score of nuclear positivity. Then, a larger group of grade 3 meningiomas (n=44) was examined to determine the prognostic value of EZH2 expression. We investigated the effect of the EZH2 inhibitor EPZ6438 (10-40 µM) in the IOMM-Lee cell line. Cell growth was characterized using the alamarBlue (AB) and sulforhodamine-B (SRB) assays. Finally, the effect of EPZ6438 (p.o. 250 mg / kg BID for 9 days) was also tested in an IOMM-Lee heterotopic xenograft model, in SCID mice.
EZH2 immunopositivity was significantly higher in grade 2 than in grade 1 and in grade 3 than in grade 2 meningiomas. Tumors in the larger grade 3 cohort were divided into EZH2-low and EZH2-high groups based on the magnitude of the H-score relative to the median value. Both progression-free and overall survival were significantly shorter in EZH2-high cases. IOMM-Lee cells show exceedingly high EZH2 expression based on our IHC studies. Treatment with EPZ6438 exerted a significant, dose-dependent inhibitory effect on cell growth as assessed by both AB and SRB tests. IOMM-Lee tumor growth was also significantly inhibited by EPZ6438 treatment in the xenograft model.
Our IHC studies confirm that EZH2 expression increases with the progression of meningiomas. Moreover, in grade 3 meningiomas, higher EZH2 expression is associated with a worse prognosis. The inhibitory effect of EPZ6438 on IOMM-Lee cell growth both in vitro and in vivo suggests that EZH2 inhibitors may represent a promising new option in grade 3 meningiomas.
Funding: NKFIH-PD-146549.