Harnessing YAP-TEAD Activity as Anti-Invasion Therapeutic in Human Glioblastoma

Icahn School Of Medicine At Mount Sinai, New York NY

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Abstract

Project Summary: Current glioblastoma (GBM) therapy fails to target the invasive nature of tumor spread, responsible for recurrence and disease progression. A better understanding of tumor biology at the infiltrative margin, and improved combination therapy that targets not only proliferation but also migration, is urgently needed for all GBM patients. For the past decade, our group has been at the forefront of focused efforts to elucidate further the biology of glioma migration and supported through this R01 we have implicated the important role of Hippo effectors YAP/TAZ-TEAD as anti-invasive GBM targets. The Hippo pathway integrates complex chemical, cytoskeletal and mechanical cues related to cell movement, which converge on the nuclear translocation of the YAP oncoprotein, or its paralog TAZ, and their co-activation of the TEAD family of transcription factors. Our lab uncovered TEAD1 as a critical driver of migration in glioma stem-like populations, and subsequently showed anti-invasive and survival efficacy of the YAP-TEAD inhibitor Verteporfin (VP) in primary and recurrent GBM models, as monotherapy or in combination with standard-of-care (SOC) therapy, the latter potentially resensitizing chemoresistant tumor cells to Temozolomide (TMZ). In parallel, others have shown YAP/TAZ as critical drivers of stemness and plasticity in GBM, supporting the exciting overarching hypothesis that oncogenic convergence on YAP-TEAD can be harnessed as new and effective GBM therapy. With VP progressing to phase I/II trials in recurrent EGFR-mutant GBM patients, our studies advance several urgent and clinically relevant limitations regarding the need for new therapeutic strategies, such as oral drug administration of YAP-TEAD inhibitors in an outpatient setting; the preclinical efficacy of such therapy across GBM subtypes, including in primary and in non EGFR-mutant GBM, in combination with SOC therapy; and the necessity to establish rational biomarkers of response for YAP-TEAD inhibitors that assess both tumor cells and their microenvironment at the infiltrative margin, the niche that recapitulates best the residual disease being targeted by oncologists. Leveraging our expertise and preliminary data, we address these in three translational aims: 1) Repurpose new YAP-TEAD inhibitors with oral bioavailability, including nanoVP and Vivace (VT) formulations with superior pharmacodynamics and pharmacokinetics (PK/PD), for future clinical use in GBM; 2) Predict synergy of VP/VT with standard-of-care therapy across primary and recurrent GBM; 3) Define YAP-TEAD vulnerabilities at the margin as biomarkers of durable treatment response. We use innovative single-cell resolution spatial transcriptomics, matched primary/recurrent preclinical GBM models and human samples, and uniquely focus on biology at the infiltrative margin. This analysis will define biomarkers of response in clinically optimized YAP-TEAD inhibitors relevant for ongoing VP/VT clinical trials and elicit which GBM is most likely to benefit from combination therapy with SOC, justifying expansion of trial eligibility criteria.