Targeting the EGFR Signaling Network in Glioblastoma
Abstract
Glioblastoma (GBM) is a uniformly fatal cancer with very few treatment options. Epidermal growth factor receptor (EGFR) is the most frequently altered oncogenic pathway in GBM (~60%), and therefore is a compelling target for this devastating disease. Despite overwhelming evidence of the importance of EGFR in GBM, all previous clinical studies of EGFR inhibitors have failed to improve patient outcome. Our data show this is due to the fact that none of these EGFR inhibitors were designed for GBM, which requires unique characteristics for brain penetrance (must cross the blood-brain barrier) and must target the genetic alterations in EGFR that are unique to GBM, including extracellular domain mutations (e.g., EGFRvIII) and amplifications in EGFR without mutations. These distinctive features of EGFR driven GBM suggest a critical need for the development of EGFR inhibitors specifically tailored for GBM. Our interdisciplinary team has developed a series of novel, brain-penetrant EGFR inhibitors specifically designed for EGFR-driven GBM. From over 80 compounds synthesized, ERAS-801 displayed substantial brain penetration with high potency and selectivity against EGFR-altered GBM. Consequently, ERAS-801 had substantially longer survival in preclinical GBM models relative to conventional (e.g., erlotinib, lapatinib) and next-generation (e.g., Tagrisso) EGFR inhibitors. Based on these exciting results, ERAS-801 is now in early phase clinical for GBM patients. While our results are stimulating, we are aware there is a universally high failure rate for new drugs in GBM. Therefore, we are proposing an innovative study design that leverages an early phase clinical trial of ERAS-801, combined with our innovative preclinical GBM models, to concurrently (1) evaluate a noninvasive, metabolic imaging biomarker of treatment response; (2) study the biological changes that occur after acquired resistance (failure) of ERAS-801; and (3) test whether a combination treatment with ERAS-801 and a drug that inhibits of the anti-apoptotic protein BCL-xL enhance intrinsic GBM cell death. We believe our unique, personalized medicine approach to designing and studying disease-tailored therapeutics and biomarkers in the context of early phase clinical trials can provide a framework for efficiently studying new treatments in rare diseases including, but not limited to, GBM. As brain tumors are the third leading cause of cancer deaths in the active U.S. military, with GBM being the most lethal type of brain tumor, this project will directly address the fiscal year 2022 Peer Reviewed Cancer Research Program Topic Area of Brain Cancer and the Overarching Challenges consisting of Therapeutics and Diagnostics. The potential benefits to patients with GBM will include a novel therapeutic that targets one of the most altered genes in brain cancer, together with a noninvasive companion biomarker to rapidly predict outcome. Together, our proposal will accelerate biomarker and drug optimization development for ERAS-801 that, if achieved, will have an immediate impact on the outcomes of the majority of patients with GBM.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310899
Entities
People
- Benjamin M Ellingson
Organizations
- United States Army
- University of California, Los Angeles