Explore UAB

UAB Department of Radiation Oncology researchers have identified potential targets to help overcome therapy-resistant tumors in patients with glioblastoma (GBM), the most common and devastating form of primary brain cancer. Dr. Christopher Willey

UAB Department of Radiation Oncology Hale-Stephens ROAR Endowed Professor Christopher Willey, M.D., Ph.D., with co-authors, recently published the research, “An in vivo model of glioblastoma radiation resistance identifies long noncoding RNAs and targetable kinases” in the peer-reviewed journal JCI Insight.

“This project is focused on a real clinical problem we face in treating glioblastoma and that is acquired therapeutic resistance,” Dr. Willey said.

The current standard of care for this disease is surgery, if possible, followed by radiation and chemotherapy.

“Unfortunately, the tumor pretty much universally recurs and the median survival is only 15 months from diagnosis,” Dr. Willey said.

While there is much research on radiation resistance for GBM, Dr. Willey said most tumor models used in studies have never actually seen therapy before. “There is a lack of acquired therapeutic resistance models, particularly radiation, and we sought to improve upon that,” he said.

The new article explains how researchers used a patient-derived xenograft program, or PDX, for this disease to generate some acquired radiation resistance models that they then profiled to try to identify potential pathways of resistance.

Researchers were successful in generating phenotypically and molecularly diverse models of GBM tumor recurrence, particularly related to radiation.

They also identified alterations in long noncoding RNA transcripts (lncRNAs) in the acquired radiation-resistant PDX lines, which were associated with several gene expression signatures (e.g., cell cycle, stemness, and DNA damage response) suggesting that lncRNAs could potentially regulate pathways that lead to radiation resistance.

“And particularly important, kinomic profiling from these models reveals potential targets for therapeutic development for GBM recurrence,” Dr. Willey said.

Watch Dr. Willey’s Author's Take video for JCI Insight. Look for a summary of this article in the September 2022 "JCI This Month" print digest.

Co-authors from the UAB Heersink School of Medicine include: Christian T. Stackhouse, Department of Radiation Oncology and Department of Neurosurgery; Joshua C. Anderson, Nicholas J. Eustace, Chuan Xing, Hasan Alrefai, Kevin J. Lee, and Eddy S. Yang, Department of Radiation Oncology; Zongliang Yue, Jelai Wang, and Jake Y. Chen, Informatics Institute; Catherine P. Langford and G. Yancey Gillespie, Department of Neurosurgery; Fady M. Mikhail, Department of Genetics; Ryan E. Bash and C. Ryan Miller, Division of Neuropathology, Department of Pathology; and Anita B. Hjelmeland, Department of Cell, Developmental, and Integrative Biology.

Other co-authors include: Xiangqin Cui, Emory University Rollins School of Public Health Department of Biostatistics and Bioinformatics; James R. Rowland IV, The Ohio State University Department of Physics.