The grant will fund research surrounding next-generation human models that could potentially aid in the development of treatment for glioblastoma.A researcher from the University of Alabama at Birmingham Department of Pathology recently received a $3.09 million R01 grant 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.

C. Ryan Miller, M.D., Ph.D., the Vishnu Reddy Translational Research Endowed Professor and division director of Neuropathology, received funding from the National Cancer Institute for the grant, titled “Credentialing next-generation human glioma models for precision therapeutics,” for research over the next five years.

“Many preclinical studies sound promising; but when they try them in the clinic, they don’t work,” Miller said. “We’re focused on precision oncology. To give the right patient the right drug at the right time, you have to do molecular diagnostics.”

Patients with glioblastoma are typically treated with surgery, followed by radiation and a drug, temozolomide, that Miller calls, a “DNA-damaging agent.” With no treatment whatsoever, average patient life expectancy from diagnosis is three to six months; radiation may add six to nine months and chemotherapy another three months.

Miller’s research aims to identify the genetic abnormalities of these tumors and target those with new drugs. The target they are interested in is the epidermal growth factor receptor or EGFR gene, which provides instructions for making a receptor protein that can bind with other proteins in the body to help the cell respond to its environment. EGFR is key to one of the so-called “hallmarks of cancer,” namely sustaining proliferative signaling, or fueling cancer growth.

In the mid-2000s, clinical trials were conducted on GBM using first-generation EGFR tyrosine kinase inhibitors, which is a targeted therapy that identifies and attacks specific types of cancer cells while causing less damage to normal cells. These clinical trials used TKIs for GBM because of their success with EGFR-driven lung cancer. However, researchers have since learned that the drugs tested did not penetrate the brain very well, and that the biology of EGFR is very different between the lung and the brain, including the location of mutations.

“The research showed that we are unable to give glioblastoma patients a drug designed to treat a non-brain tumor,” Miller explained. “There’s a blood-brain barrier that prevents drugs from getting in in the first place.”

Miller says another challenge to treating these aggressive tumors is that most clinical trials for cancer are conducted for patients with recurring tumors.

“This changes the genetics and the biology of the tumor,” Miller explained. “We have to treat patients with newly diagnosed disease so that we can perform molecular tests on their surgically removed tumors in order to guide therapy.”

C. Ryan Miller, M.D., Ph.D
Photography: Lexi CoonUsing modeling technology from co-Principal Investigator Frank Furnari, Ph.D., at the University of California-San Diego and patient-derived tumor models from UAB, Donald O’Rourke, M.D., co-PI at the University of Pennsylvania, and collaborator Jann Sarkaria, M.D., at the Mayo Clinic, Miller will develop a series of genetically engineered human tumor models they can place in immune-deficient animal models that will not reject the tumors. They can then control the mutations that drive tumor growth, to understand specific mechanisms of the drugs designed to treat them.

Miller says the factor that interested him in this study initially was the attractiveness of EGFR as a therapeutic target in GBM.

“What we bring to the table is the molecular credentialing that allows us to look at all of the characteristics of this tumor together,” Miller said. “By studying the characteristics of GBM, we can get an idea of how these tumors might become drug-resistant. We are working to ensure every glioblastoma diagnosis would also get genetic testing for EGFR mutations.”

Two of Miller’s co-investigators on the grant, David Nathanson, Ph.D., and Tim Cloughesy, M.D., both at the University of California at Los Angeles, have developed a series of EGFR TKI candidates for the explicit purpose of targeting EGFR-driven GBM. These drugs are promising, Miller says, because they are highly brain-penetrant, can potently target both normal EGFR and the various mutant forms of the receptor, and have limited off-target effects. The UCLA team recently reported the discovery of JCN037, an EGFR TKI that fulfills all of these properties.

Other members of the research team include co-investigators Anita Hjelmeland, Ph.D., associate professor, UAB Department of Cell, Developmental, and Integrative Biology, and Jake Chen, Ph.D., professor of genetics and chief bioinformatics officer of the Informatics Institute at UAB; Zev Binder, M.D., Ph.D., and Hongjun Song, Ph.D., at the University of Pennsylvania; and Gary Johnson at the University of North Carolina.

If the research goes as planned, says Miller, who is a senior scientist with the O’Neal Comprehensive Cancer Center, the multi-institutional team plans to conduct a clinical trial where they would screen patients for specific mutational profiles, including EGFR, and give them a new, updated version of the JCN037 drug.