Abstract 1662: Evaluation of TEAD inhibitor, VT03989 treatment on growth of aggressive meningioma preclinical models

Abstract

Abstract Background: Aggressive meningiomas (WHO grade II/III) are incurable brain tumors and despite surgery and radiation therapy, tumors recur frequently without approved systemic treatment options. Hence, there is an unmet need for targeted inhibition therapy and biomarkers that predict vulnerability to targeted therapies in aggressive meningioma patients. Hippo signaling pathway has been shown to be dysregulated in meningioma, resulting in activation of its target TEAD as a transcriptional factor. We hypothesize that targeted inhibition of TEAD in recurrent high-grade meningioma with NF2 loss will lead to increased inhibition of tumor growth. Here, we investigated the effect of VT3989, a potent TEAD inhibitor, in meningioma cell lines with NF2 wild-type or NF2 loss genotype. Methods: Two meningioma cell-lines: IOMM-Lee (NF2 wild-type) and MG309, a grade III meningioma patient-derived cell line with NF2 loss were treated with various doses of VT3989 and cell viability was assessed. Relative expression of direct targets of TEAD including CTGF and CYR61 was determined with quantitative PCR (qPCR) to ensure target engagement. Global transcriptomic changes were examined via RNAseq analysis on RNA isolated from MG309 cells treated with VT03989 compared to vehicle treated cells. Results: VT3989 treatment significantly decreased viability of both IOMM-Lee and MG309 cells. Canonical downstream targets of TEAD such as CTGF, CYR61, BIRC5, BCL-2 were downregulated in VT3989 treated cells compared to control. Furthermore, VT03989 treatment resulted in downregulation in cell cycle regulation and DNA damage response (DDR) pathway genes. Ongoing work is focused on combining VT3989 with agents targeting cell cycle and DDR pathways. Conclusion: VT3989 treatment led to downregulation of TEAD direct targets CTGF and CYR61 and inhibited cell viability of both IOMM-Lee cell and MG309 meningioma lines. RNA-seq analysis identified cell cycle and DDR pathway genes to be downregulated upon TEAD inhibition. Citation Format: Siddhi Desai, Anil Thaghalli Shivanna, Mariya Stavnichuk, Elizabeth Hayes, Sonam Patel, James McNamara, Anita DeSantis, Nader Sanai, An-Chi Tien, Shwetal Mehta. Evaluation of TEAD inhibitor, VT03989 treatment on growth of aggressive meningioma preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1662.