The diffusely infiltrative growth and spread in glioblastoma (GBM) impedes gross-total resection and chemoradiation. Tumor proliferation in GBM has been frequently related to aberrant activation of receptor tyrosine kinase (RTK) signaling. The Hippo pathway also regulates tissue growth and cell fate, and the dysregulation of its downstream effectors YAP1-TEAD has been implicated in tumor invasion, metastasis, and chemoresistance in RTK/RAS-driven carcinomas. The role of Hippo signaling and RTK crosstalk in GBM is still poorly understood. Monotherapy clinical trials with mutation-targeted kinase inhibitors, despite some success in other cancers, have yet to impact GBM. Besides insufficient blood–brain barrier penetration, combinations are key to overcoming obstacles such as intratumoral heterogeneity, adaptive resistance, and the epistatic nature of tumor genomics that cause mutation-targeted therapies to fail. This thesis explores the need for novel therapeutics exploring better predictions for drug combination therapy and targeting GBM cell migration.
With now hundreds of potential drugs, exploring the combination space clinically and preclinically is daunting. We propose a simulation-based approach that integrates patient-specific data with a mechanistic computational model of pan-cancer driver pathways to prioritize drug combinations by their simulated effects on tumor cell proliferation and death. Here we illustrate a first step, tailoring the model to 14 GBM patients from The Cancer Genome Atlas defined by an mRNA-seq transcriptome, and then simulating responses to three promiscuous FDA-approved kinase inhibitors (bosutinib, ibrutinib, and cabozantinib) with evidence for blood–brain barrier penetration. The model captures binding of the drug to primary targets and off-targets based on published affinity data and simulates responses of 100 heterogeneous tumor cells within a patient. Drug combinations tend to be either cytostatic or cytotoxic, but seldom both, highlighting the need for considering targeted and nontargeted therapy.
Recently, our lab defined a regulatory chromatin accessibility signature centered around the TEAD transcriptional family, which relates specifically to tumor migration in uncultured, patient-derived GBM stem cell populations, and we functionally validated TEAD1 as a driver of GBM migration, both in-vitro and in-vivo. Moreover, we found TEAD1 to be a direct transcriptional target of EGFR. To further characterize the effect of Hippo-TEAD on GBM migration and its interaction with EGFR/RTK signaling, we treated patient-derived GBM cells with Verteporfin (VP), an FDA-approved macular degeneration therapy, and a small-molecule inhibitor of the YAP/TEAD complex with proven anticancer efficacy. VP treatment inhibited not only GBM cell growth but also impaired tumor migration both in vitro and in vivo. VP penetrated into the brain parenchyma, and resulted in lower tumor burden without systemic toxicity in orthotopic xenograft mouse models. The inhibitory effect of Verteporfin on RTK signaling and GBM migration, and its brain penetrance at non-toxic levels in vivo, underscore potential future therapeutic value for this drug in GBM patients.
|Advisor:||Birtwistle, Marc, Tsankova, Nadia|
|Commitee:||Sobie, Eric, Schlessinger, Avner, Friedel, Roland, Canoll, Peter|
|School:||Icahn School of Medicine at Mount Sinai|
|Department:||Pharmacology and System Biology|
|School Location:||United States -- New York|
|Source:||DAI-B 81/6(E), Dissertation Abstracts International|
|Subjects:||Cellular biology, Oncology|
|Keywords:||Cancer, Glioblastoma, Mathematical modeling|
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