Dr. C. Ryan MillerC. Ryan Miller, M.D., Ph.D., Vishnu B. Reddy Translational Research Endowed Professor, Division Director, Neuropathology, has been awarded a 4-year $2.5 million R01 grant from the National Institute of Neurological Disorders and Stroke. The grant, “Therapeutic targeting mesenchymal transition in newly diagnosed and recurrent glioblastoma,” will run through August 2028.

Glioblastoma (GBM) is the most common primary brain tumor in adults. It is a highly invasive, neurologically destructive tumor with a survival range of 12-15 months despite treatment efforts. A central issue contributing to treatment failure is the varied cell type composition of these tumors. Miller, in collaboration with Frank Furnari, Ph.D., a professor in the Division of Regenerative Medicine at the University of California San Diego’s Department of Medicine, will attempt to identify mechanisms that promote a therapy resistant tumor state.

“GBM is very aggressive and it attacks the brain in a way in which you can’t remove all of the tumor,” Miller says. “While chemotherapy and radiation extend survival, we knowDr. Frank Furnari those tumors are going to come back because we can’t remove them all to begin with. When it does come back, it’s a different disease altogether. Our goal is to pharmacologically target this state to improve therapeutic efficacy for patients with newly diagnosed and recurrent GBM.”

The research team will do this by testing a specific biochemical reaction. They will investigate whether ReIA acetylation acts as a regulatory switch that drives an inflammatory microenvironment and contributes to a treatment-resistant, mesenchymal phenotype in GBM.

“We want to take tumors in a pro-neural state and prevent them from becoming mesenchymal. For patients that are already mesenchymal, we want to reverse that using drug therapy.” 

The researchers hope to identify the mechanisms that promote a mesenchymal tumor state and nominate a new drug to target it.

With UC San Diego as the prime institution for this award, Miller and Furnari have assembled a collaborative team of investigators from seven institutions for this study. Miller’s collaborators at UAB include Brittany Lasseigne, Ph.D., Cell, Developmental and Integrative Biology, Christopher Willey, M.D., Ph.D., Radiation Oncology, and Burt Nabors, M.D., Neuro-Oncology. Furnari’s UC San Diego team includes Adam Engler, Ph.D., Shaochen Chen, Ph.D., Fleur Ferguson, Ph.D., and Keith Jenne, D.V.M. Additional collaborators include Albert Baldwin, Ph.D., University of North Carolina at Chapel Hill, Jann Sarkaria, M.D., Mayo Clinic, Susan Kaech, Ph.D., Salk Institute for Biological Studies, and David Nathanson, Ph.D., University of California, Los Angeles.