EXTH-27. YAP/TAZ TRANSCRIPTIONAL CO-ACTIVATORS CREATE THERAPEUTIC VULNERABILITY TO VERTEPORFIN IN EGFR MUTANT GLIOBLASTOMA
| Autor: | Krishanthan Vigneswaran, Nathaniel H. Boyd, Jeffrey J. Olson, Se-Yeong Oh, Shoeb Lallani, Stewart G. Neill, Renee Read, Andrew B. Boucher |
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| Rok vydání: | 2020 |
| Předmět: | |
| Zdroj: | Neuro Oncol |
| ISSN: | 1523-5866 1522-8517 |
| DOI: | 10.1093/neuonc/noaa215.381 |
| Popis: | Glioblastoma (GBM), neoplasms derived from glia and neuro-glial stem/progenitor cells, are the most common and lethal malignant primary brain tumors diagnosed in adults, with a median survival of 14 months with current treatments. GBM tumorigenicity is often driven by genetic aberrations in receptor tyrosine kinases (RTKs), such as EGFR, and the Pi-3 kinase (PI3K) signaling pathway. Using a Drosophila glioma model and human patient-derived GBM cells, we identified the YAP and TAZ transcription co-activators, effectors of the Hippo pathway that promote gene expression via TEAD co-factors, as key drivers of GBM tumorigenicity downstream of oncogenic EGFR signaling. YAP and TAZ are highly expressed in EGFR mutant human GBMs, and their knockdown in EGFR mutant GBM cells inhibits proliferation, blocks neuro-glial stem/progenitor cell fate, and elicits apoptosis. Our results indicate that YAP/TAZ-TEAD directly regulate transcription of SOX2, C-MYC, and EGFR itself to create a feedforward loop to drive survival and proliferation as well as stem/progenitor cell fate in human GBM cells. Moreover, the benzoporphyrin derivative verteporfin, a disruptor of YAP/TAZ-TEAD mediated transcription, specifically induced apoptosis of cultured patient-derived GBM cells, suppressed expression of YAP/TAZ transcriptional targets, including EGFR, and conferred significant survival benefit in an orthotopic xenograft GBM model. Our efforts led us to design and initiate a phase 0 clinical trial of Visudyne, an FDA-approved liposomal formulation of verteporfin, where we used intraoperative fluorescence to observe and verify verteporfin uptake into tumor cells in GBM tumors in human patients. Together, our data indicate that verteporfin is a promising therapeutic agent for EGFR amplified and mutant GBM. On the basis of these results, we have initiated as phase 1/2 clinical trial of Visudyne in patients with recurrent GBM characterized by EGFR amplification and/or mutation. |
| Databáze: | OpenAIRE |
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