Small molecule targets glioblastoma oncogene in preclinical studies

UVA Comprehensive Cancer Center scientists have identified a molecule that blocks the gene responsible for glioblastoma, raising hopes that the molecule could become a much-needed new treatment for the deadliest brain cancer. 

Researcher Hui Li, PhD, previously discovered the "oncogene" responsible for glioblastoma, a cancer for which there are no treatments that extend life for more than a few months. In his follow-up work, published in Science Translational Medicine, Li reports the identification of a small molecule that blocked the gene's activity in both cell samples and lab mice. In mice, the molecule proved effective without unwanted or harmful side effects.

While more work needs to be done before the molecule could be used as a treatment in people, the results so far are promising and suggest the compound could prevent the invasive cancer from threading its way through the brain, Li says. 

Glioblastoma is a devastating disease. Essentially no effective therapy exists. What's novel here is that we're targeting a protein that GBM cells uniquely depend on, and we can do it with a small molecule that has clear in vivo activity. To our knowledge, this pathway hasn't been therapeutically exploited before."

Hui Li, PhD, University of Virginia School of Medicine's Department of Pathology

About glioblastoma

Glioblastoma is a fast-growing form of brain cancer that is almost always deadly. Typical survival after diagnosis is only about 15 months, and more than 14,000 Americans are diagnosed every year. Treatment options include surgery, but the way the cancer proliferates through the brain makes it difficult to remove. Other treatments include chemotherapy and radiotherapy, but they only extend the survival for a few months. These treatments can also greatly affect quality of life, so some patients opt out of treatment altogether.

The difficulty of treating the disease, and the limited benefits of the available treatments, means new options are desperately needed. Li's line of research, he hopes, could produce a more effective alternative.

Li first discovered the oncogene – a cancer-causing gene – responsible for glioblastoma in 2020. That gene, AVIL, normally helps cells maintain their size and shape. But the gene can be shifted into overdrive by a variety of factors, the researchers found. This causes cancer cells to form and spread.

At the time, the researchers found that blocking the gene's activity could completely destroy glioblastoma cells in lab mice, without any effect on healthy cells. But the lab technique they used to determine that is unsuitable for use in people. That put them on the hunt for a molecule that could stop the gene's harmful effects.

Their pursuit has confirmed the role of AVIL in glioblastoma. The researchers found that the protein the gene produces is hardly found in the healthy human brain but is abundant in patients with glioblastoma.

The scientists used a technique called "high-throughput screening" to quickly and efficiently evaluate many compounds for their potential to block AVIL activity. The molecule they have found appears to affect only tumor cells, sparing healthy brain tissue. Further, the molecule can cross the brain's protective barrier that keeps out many potential treatments for neurological diseases. 

As a treatment, the compound could be taken by mouth, like any other prescription pill, the researchers say.

Before the compound could become available for patients, much additional research will need to be done to optimize the molecule for use in people. If all goes according to plan, the resulting drug would then be tested extensively in human volunteers before the federal Food and Drug Administration decides whether it is sufficiently safe and effective to be offered as a treatment.

While there is much more work to be done, Li and his colleagues are excited by the promise of their latest findings.

"GBM patients desperately need better options. Standard therapy hasn't fundamentally changed in decades, and survival remains dismal," he said. "Our goal is to bring an entirely new mechanism of action into the clinic - one that targets a core vulnerability in glioblastoma biology."

Findings published

Li's research team consisted of Zhongqiu Xie, Pawel Ł. Janczyk, Robert Cornelison, Sarah Lynch, Martyna Glowczyk-Gluc, Becky Leifer, Yiwei Wang, Philip Hahn, Johnathon D. Dooley, Adelaide Fierti, Xinrui Shi, Yiyu Zhang, Tingxuan Li, Qiong Wang, Zhi Zhang, Laine Marrah, Angela Koehler, James W. Mandell, Michael Hilinski and Li. 

The research was supported by the National Institutes of Health, grants R01CA240601 and R01CA269594, and by the Ben & Catherine Ivy Foundation.

Li has founded a company, AVIL Therapeutics, to develop AVIL inhibitors. He and Xie also have obtained a patent related to the approach. 

Finding new ways to improve patient care is a core mission of both UVA Comprehensive Cancer Center and UVA's Paul and Diane Manning Institute of Biotechnology. UVA Comprehensive Cancer Center is one of only 57 cancer centers in the country to earn the "comprehensive" designation from the National Cancer Institute in recognition of their exceptional patient care and cutting-edge cancer research.

The Manning Institute, meanwhile, has been launched to accelerate the development of new treatment and cures for the most challenging diseases. This will be complemented by a statewide clinical trials network that expands access to potential new treatments as they are developed and tested.