Anti-invasive efficacy and survival benefit of the YAP-TEAD inhibitor verteporfin in preclinical glioblastoma models

Anne Marie Barrette, Halle Ronk, Tanvi Joshi, Zarmeen Mussa, Meenakshi Mehrotra, Alexandros Bouras, German Nudelman, Joe Gerald Jesu Raj, Dominique Bozec, William Lam, Jane Houldsworth, Raymund Yong, Elena Zaslavsky, Constantinos G. Hadjipanayis, Marc R. Birtwistle, Nadejda M. Tsankova

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Background: Glioblastoma (GBM) remains a largely incurable disease as current therapy fails to target the invasive nature of glioma growth in disease progression and recurrence. Here, we use the FDA-approved drug and small molecule Hippo inhibitor Verteporfin (VP) to target YAP-TEAD activity, known to mediate convergent aspects of tumor invasion/metastasis, and assess the drug's efficacy and survival benefit in GBM models. Methods: Up to 8 low-passage patient-derived GBM cell lines with distinct genomic drivers, including 3 primary/recurrent pairs, were treated with VP or vehicle (VEH) to assess in vitro effects on proliferation, migration, invasion, YAP-TEAD activity, and transcriptomics. Patient-derived orthotopic xenograft (PDX) models were used to assess VP's brain penetrance and effects on tumor burden and survival. Results: VP treatment disturbed YAP/TAZ-TEAD activity; disrupted transcriptome signatures related to invasion, epithelial-to-mesenchymal, and proneural-to-mesenchymal transition, phenocopying TEAD1-knockout effects; and impaired tumor migration/invasion dynamics across primary and recurrent GBM lines. In an aggressive orthotopic PDX GBM model, short-term VP treatment consistently diminished core and infiltrative tumor burden, which was associated with decreased tumor expression of Ki67, nuclear YAP, TEAD1, and TEAD-associated targets EGFR, CDH2, and ITGB1. Finally, long-term VP treatment appeared nontoxic and conferred survival benefit compared to VEH in 2 PDX models: As monotherapy in primary (de novo) GBM and in combination with Temozolomide chemoradiation in recurrent GBM, where VP treatment associated with increased MGMT methylation. Conclusions: We demonstrate combined anti-invasive and anti-proliferative efficacy for VP with survival benefit in preclinical GBM models, indicating potential therapeutic value of this already FDA-approved drug if repurposed for GBM patients.

Original languageEnglish
Pages (from-to)694-707
Number of pages14
JournalNeuro-Oncology
Volume24
Issue number5
DOIs
StatePublished - 1 May 2022

Keywords

  • Verteporfin
  • YAP-TEAD
  • invasion
  • migration
  • preclinical

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