Repurposing the drug verteporfin as anti-neoplastic therapy for glioblastoma
Renee Read
Abstract
Glioblastoma (GBM) is the most common and deadly primary malignant brain tumor in adults and is characterized by rapid growth and diffuse infiltration. Even with current treatment strategies consisting of aggressive surgical resection followed by chemotherapy and radiation, GBM evades treatment and recurs due to remaining therapy-resistant cell populations, including infiltrative self-renewing neural stem cell-like GBM stem cells (GSCs). Thus, there is a pressing need to identify new treatment strategies for GBM. Surmounting this challenge depends on exploiting our understanding of the biological drivers of tumor formation and progression for therapeutic purposes. GBMs have been subject to extensive molecular characterization, which show that frequent alterations in tumor cells include overexpression, amplification, and/or mutation of receptor tyrosine kinases (RTKs), such as epidermal growth factor receptor (EGFR), in IDH1 wild-type tumors. A recent study from Tome-Garcia et al showed that the TEAD transcription factors are important regulators of cell migration in EGFR-expressing infiltrative GSCs.1 TEAD family transcription factors directly bind to DNA and stimulate expression of transcriptional target genes in response to binding by the paralogous transcriptional co-activators YAP and TAZ, which are inactivated by the Hippo pathway and activated by RTK pathways.2 Several recent studies have reconstructed transcriptional regulatory networks associated with GSC identity and functionality, and these studies have identified YAP and TAZ as master transcriptional determinants that define GSC populations induced downstream of well-established oncogenic drivers of GBM,3–6 such as RTKs including EGFR. Together with Tome-Garcia et al, these studies establish that TEAD-dependent YAP/TAZ transcriptional targets in GSCs include gene expression programs that govern epithelial-to-mesenchymal transition, migration, and neural differentiation, and stem/progenitor cell self-renewal and proliferation, including EGFR itself.1,4,5 In nervous system development, YAP and TAZ are expressed in radial glia and cortical and ependymal neural stem/progenitor cells, where they are required for TEAD-dependent proliferation, expansion, and structural organization of these cell types during neurogenesis.7 Thus, YAP/TAZ-TEAD recapitulate their neurodevelopmental roles in GBM, and drive an EGFR-mediated feedforward loop that promotes the pathogenic properties of GSCs.