Abstract 3789: Therapeutic targeting of the YAP/TAZ pathway in glioblastoma with verteporfin

Abstract

Glioblastoma (GBM) is a particularly lethal brain neoplasm accounting for half of malignant primary brain tumors diagnosed in adults and maintains a devastating diagnosis, with a median survival of 14 months despite standard clinical interventions of surgical, chemotherapeutic, and radiation treatments. GBM tumorigenicity is often driven by 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 glioma cells, we identified YAP/TAZ, effectors of the Hippo pathway that promote expression of stemness factors and oncogenes via activation of the TEAD transcription factors, as drivers of glioma tumorigenicity. This led to the discovery that YAP/TAZ are highly expressed in human patient-derived glioma stem cells and that knockdown of these inhibits cell growth. We hypothesized that Verteporfin, a benzoporphyrin derivative approved by the FDA for the treatment of macular degeneration, may have therapeutic benefit for glioblastoma due to its published ability to inhibit interaction between YAP and TEAD transcription factors. Using in vitro culture-based assays and in vivo in GBM xenograft models, we observed Verteporfin specifically induces apoptosis in GBM cells, slows tumor growth, and durably suppressesexpression of known and novel TEAD transcriptional targets in tumor tissue. We validated several direct targets using chromatin immunoprecipitation, and are seeking to further identify the full transcriptional program controlled by YAP/TAZ-TEAD in GBM. Our efforts have led to a phase 0 clinical trial where we were able to observe Verteporfin uptake in GBM tumors in human patients. These data indicate that Verteporfin is a promising therapeutic target for GBM. Citation Format: Nathaniel H. Boyd, Krish Vigneswaran, Shoeb Lallani, Se-Yeong Oh, Andrew Boucher, Jeffrey Olson, Renee Read. Therapeutic targeting of the YAP/TAZ pathway in glioblastoma with verteporfin [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 3789.

Emerging roles for the YAP/TAZ transcriptional regulators in brain tumour pathology and targeting options

“…It induces apoptosis and suppresses YAP/TAZ transcriptional targets of EGFR‐amplified or EGFR‐mutant GBM cells 111 . Most notably, the administration of Visudyne, which is an Food and Drug Administration (FDA)‐approved version of verteporfin, led to its absorption from GBM cells in patients with suspected or known recurrent GBM, further accentuating the potential implementation of verteporfin in the therapeutic strategies against GBM 128 …”