Background Glioblastoma (GBM) remains a largely incurable disease as current therapy fails to target the invasive nature of GBM growth in disease progression and recurrence. Here we use the FDA-approved drug and small molecule Hippo inhibitor Verteporfin 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 eight low-passage patient-derived GBM cell lines with distinct genomic drivers, including three primary/recurrent pairs, were treated with Verteporfin or vehicle to assess in-vitro effects on proliferation, migration, YAP-TEAD activity, and transcriptomics. Patient-derived orthotopic xenograft models (PDX) were used to assess Verteporfin’s brain penetrance and effects on tumor burden and survival. Results Verteporfin 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 Verteporfin 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 Verteporfin treatment appeared non-toxic and conferred survival benefit compared to vehicle in two 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 Verteporfin with survival benefit in preclinical GBM models, indicating potential therapeutic value of this already FDA-approved drug if repurposed for glioblastoma patients.

BACKGROUND Because minimizing injury to critical brain regions during high-grade glioma (HGG) surgery is essential, the optimal extent of resection (EOR) for any given patient is often less than 100% of the tumor bulk. However, there are no accepted methods of assessing the upper limit of EOR. Advances in whole-brain tractography (WBT) present an opportunity to address this problem. Here, we develop a predictive model for surgical outcomes in HGG as classified by WHO CNS5, and leverage it to determine the added utility of a WBT-based volumetric resectability metric. METHODS We included patients who underwent biopsy or resection of a new or recurrent HGG by the senior author from 2013 to 2020. A volumetric tumor analysis method incorporating WBT was developed to calculate EOR and unresectable tumor volume (UTV). Using perioperative clinical data, multiple linear and Cox regression models were used to identify independent predictors of EOR and progression-free survival (PFS). RESULTS A total of 151 HGGs were included. Median EOR and PFS were 97.0% and 5.0 months, respectively. Greater EOR strongly predicted longer PFS overall (hazard ratio [HR]=0.21, 95% confidence interval [CI] 0.07-0.72), with the largest PFS benefit observed at > 85% EOR. When controlling for EOR, higher residual tumor volume (RTV) predicted longer PFS (HR=0.97, 95% CI 0.94-0.99), suggesting the existence of an RTV threshold below which PFS decreases. Involvement of eloquent regions (p=0.0086) and brainstem (p=0.0006) as categorical variables predicted lower EOR but failed to predict shorter PFS. Calculation of UTV based on actual or imputed WBT data was feasible and reliably predicted EOR. CONCLUSION Existing methods of measuring HGG resectability are poorly reproducible and do not independently predict survival. Preoperative measurement of WBT-based UTV, by substituting for EOR, may simplify and improve HGG outcome prediction, allowing neurosurgeons to better assess the surgical candidacy of individual patients.