Abstract 6384: TEAD inhibition reduces tumor proliferation in Merlin null meningioma and schwannoma

Abstract

Abstract Introduction: Meningiomas are the most common intracranial tumor and arise from the arachnoidal cell layer of the meninges. Schwannomas develop from Schwann cells which provide myelin and trophic support in the peripheral nerves. The tumor suppressor Merlin is deleted in approximately 50-60% of meningiomas and 70% of schwannomas. Loss of Merlin results in dysregulation of the Hippo pathway and consequent aberrant activation of the transcriptional coactivators YAP and TAZ. Nuclear localisation of YAP and TAZ has been shown to drive tumor phenotypes in many cancers. The TEAD family of transcription factors are major targets of YAP and TAZ-dependent signaling. TEAD family members undergo autopalmitoylation and this modification is required for transcriptional activation by YAP or TAZ. Vivace therapeutics have identified small molecule inhibitors of autopalmitoylation that block the interaction of TEAD family members with YAP and TAZ. This study seeks to establish the efficacy of small molecule inhibitors of TEAD activity in meningioma and schwannoma tumor cells. Experimental Procedures: Meningioma cell lines, primary human meningioma and schwannoma cells, as well as a schwannoma mouse model (PerisotinCRE /NF2 fl/fl) were treated with Vivace inhibitors to assess their effects upon tumor cell proliferation and TEAD driven transcription. Results: TEAD inhibition significantly reduced the proliferation of the BenMen-1 meningioma cell line, as well as in primary human meningioma cells. In schwannoma, inhibitors reduced proliferation and also reduced the expression of CTGF, a target of TEAD activation in both primary human meningioma and schwannoma cells. These novel inhibitors are also currently being tested in the Periostin CRE-NF2fl/fl schwannoma mouse model to evaluate their efficacy in vivo. Conclusions: The use of these novel compounds to inhibit TEAD function shows great potential as an effective treatment for reducing the rate of cell proliferation in meningioma and schwannoma, two clinically important tumor types. Citation Format: Liyam Laraba, Julio Grimm de Guibert, Tracy T. Tang, Leonard Post, David B. Parkinson. TEAD inhibition reduces tumor proliferation in Merlin null meningioma and schwannoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6384.