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C. Ryan Miller, M.D., Ph.D., Vishnu Reddy Translational Research Endowed Professor and Division Director, Neuropathology, published a review article in the journal Neuro Oncology on September 19 with colleagues on EGFR, the epidermal growth factor receptor, arguing for its role in precision oncology treatment of glioblastoma (GBM), a currently untreatable form of brain cancer.

"EGFR, the Lazarus target for precision oncology in glioblastoma," is a review focused on a topic Miller wished to study for years, but received multiple rejections for grant applications on the topic before finally obtaining funding this January. 
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"The criticisms of the grant during its maturation phase were that EGFR was basically a dead topic in GBM—the clinical trials had been done, they were negative, and therefore we should move on," Miller says. "We’re arguing that that conclusion is scientifically nihilistic and it would be premature to abandon it."

Miller, who was named co-director of the UAB Graduate Biomedical Sciences Neuroscience Theme in July, was awarded a $3.09 million R01 grant from the National Cancer Institute (NCI) in January to research next-generation human models to improve the development of drugs targeting glioblastoma. Glioblastoma is a complex, deadly and treatment-resistant cancer that is estimated to take approximately 10,000 lives in the United States per year, according to the National Brain Tumor Society.

The article received an "Editor's Choice" designation from the journal, and Dr. Maya Graham interviewed graduate student Benjamin Lin and Drs. David Nathanson, Frank Furnari and C. Ryan Miller about the recent manuscript on the journal's podcast.

In the article, Miller and team give the example of the RAS gene—the first oncogene (a gene which, in certain circumstances, can transform a normal cell into a tumor cell), discovered 40 years ago—that is present in 90 percent of the pancreatic tumors, Miller says. It was considered undruggable because of its structure, Miller says, but then the NCI started the "RAS Initiative, where a researchers from academia, government and industry got together to work on this as a common goal."

The product of that work, he says, is a drug for one specific mutation of KRAS. The scientists researching RAS before this, "had the same type of argument made against them that we are facing with EGFR and GBM," he says.

In GBM, EGFR is the most common oncogene that is altered, Miller says. Several trials back in early 2000s tested small molecules repurposed from lung cancer, not brain, in GBM.

“The drugs that have been tested to date on EGFR do not reach levels high enough in the brain to even modulate the receptor’s enzymaticactivity," he says, "so I consider those trials false negatives because they don’t prove that there was a biologic effect on the receptor and its downstream pathways."

In the review article, Miller and co-authors describe what is unique about EGFR biology in the context of GBM in relation to other tumor types, most notably lung. They describe the negative clinical trials with small molecule inhibitors, as well as biologics.

"We’re trying to make the argument that we need to continue to work on this target because it’s so prevalent and because we have learned so much more about its unique biology in GBM," he says.