Abstract 1111: Verteporfin inhibits GBM growth and migration and confers survival benefit in xenograft models
Authors: Barrette Anne Marie , Bouras Alexandros , Nudelman German , Bozec Dominique , Shakawat Noshin , Zaslavsky Elena , Hadjipanayis Constantinos , Birtwistle Marc R. , Tsankova Nadejda M. 
Published: September 2020

Abstract
The diffusely infiltrative growth and spread, complex molecular and oncogenic signaling aberrations, and inter-and intra-tumoral heterogeneity in glioblastoma (GBM) impedes gross-total resection and chemoradiation and highlight the need for improved tumor-specific brain-penetrant therapies that inhibit cell migration in addition to proliferation. Invasive GBM cells undergo an epithelial-mesenchymal transition (EMT) phenotypic switch, expressing higher levels of genes involved in EMT remodeling, survival, and immune response compared to non-invasive GBM tumor cells. Recently, our lab defined a regulatory chromatin accessibility signature centered around the TEAD transcriptional family, which relates specifically to tumor migration in uncultured, patient-derived GBM stem cell populations, and we functionally validated TEAD1 as a driver of GBM migration and EMT, both in vitro and in vivo. The TEAD family of transcription factors, along with their co-activators YAP/TAZ, are the main downstream effectors of the Hippo pathway, a regulator of tissue growth and cell fate whose dysregulation has been implicated in tumor invasion, metastasis, and chemoresistance in other solid tumors. Here we explored the therapeutic efficacy of Verteporfin (VP), an FDA-approved macular degeneration therapy, and a small-molecule inhibitor of the YAP/TEAD complex, in patient-derived GBM cells and orthotopic xenotransplant mouse models (PDX), assessing VP's impact on GBM proliferation and migration both in vitro and in vivo. VP treatment across three different cell lines inhibited not only glioma growth but also significantly impaired tumor migration in three different in vitro assays (live cell tracking, transwell invasion, and spheroid dispersion) in a dose-dependent manner. At the protein and whole transcriptomic levels, VP-treated cells showed dose-dependent downregulation of TEAD-target activity and significant downregulation of EMT and cell migration functional gene sets, compared to vehicle. In several independent in vivo experiments, intraperitoneal administration of VP in mice with aggressive PDX glioblastoma showed consistent drug penetration into the brain parenchyma without systemic toxicity, resulted in lower tumor burden both at the tumor core and the leading infiltrative edge (n=22 VP, n=21 VEH, p=0.02, each), showed decreased number of individual distal migratory tumor cells (n=6 VP, n=5 VEH, p=0.0001 / n=6 VP, n=5 VEH, p=0.04), and, notably, conferred a survival benefit in combination with TMZ and radiation (n=10 per condition, p=0.02). Furthermore, in PDX mice transplanted with a more typical GBM, daily administration of VP for up to 280 days conferred survival benefit even as monotherapy (n=8 per condition, p=0.02), in the absence of systemic toxicity. The inhibitory effect of Verteporfin on downstream YAP/TEAD signaling and GBM migration, and its brain penetrance at non-toxic levels, underscore potential future therapeutic value and repurposing of this drug in GBM patients.
Citation Format: Anne Marie Barrette, Alexandros Bouras, German Nudelman, Dominique Bozec, Noshin Shakawat, Elena Zaslavsky, Constantinos Hadjipanayis, Marc R. Birtwistle, Nadejda M. Tsankova. Verteporfin inhibits GBM growth and migration and confers survival benefit in xenograft models [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 1111.