Repurposing the drug verteporfin as anti-neoplastic therapy for glioblastoma.
Repurposing the drug verteporfin as anti-neoplastic therapy for glioblastoma.
复制标题
将药物维替泊芬重新用作胶质母细胞瘤的抗肿瘤治疗。
DOI：
10.1093/neuonc/noac019
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发表时间：
2022
期刊：
影响因子：
15.9
通讯作者：
Read,ReneeD
中科院分区：
文献类型：
--
作者：
Read,ReneeD
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.In this issue of Neuro-Oncology, Barrette et al build upon this work to explore the therapeutic efficacy of verteporfin, an inhibitor of YAP/TAZ-TEAD (Figure 1). 8 Verteporfin acts as a dualtargeting irreversible inhibitor of YAP/TAZ in that verteporfin binds to conserved TEAD interaction domains in YAP and TAZ to block TEAD binding and, in GSC models, provokes YAP/TAZ and TEAD protein degradation, thereby reducing nuclear localization and preventing transcriptional transactivation. 4, 8, 9 Barrette et al found that verteporfin, which downregulated YAP/TAZ-TEAD-dependent gene expression programs, reduced proliferation and viability of multiple GSC lines and standard GBM cell lines that together contain cells that represent the three different predominant transcriptional states of GBM cells, proneural, mesenchymal, and classical. Barrette et al extend on previous reports of verteporfin chemotoxicity in GBM, including Vigneswaran et al, which found that verteporfin showed no/low toxicity toward normal human neural progenitor cells but decreased YAP/TAZ-TEAD-dependent gene expression and induced apoptosis in EGFR-mutant or amplified GSCs, and reduced tumor growth in …
