Targeting stromal cells may help overcome treatment resistance in glioblastoma

February 26, 2020

PHILADELPHIA - The deadly brain cancer glioblastoma (GBM) is often resistant to chemotherapy and radiation, but new research from the Perelman School of Medicine at the University of Pennsylvania and Penn's Abramson Cancer Center shows targeting stromal cells - the cells that serve as the connective tissue of the organs - may be an effective way of overcoming that resistance. Specifically, the researchers found that GBM causes these stromal cells to act like stem cells, naturally resisting attempts to kill them and promoting tumor growth instead. They also identified the pathway that makes this all possible and showed that blocking that pathway makes cancer vulnerable in a lab setting. Science Translational Medicine published the findings today.

GBM is a particularly aggressive form of brain cancer. Most estimates show there are around 11,000 new cases each year, but the five-year survival rate is between just five and 10 percent. The tumors themselves are usually heterogeneous - meaning that different parts of the tumor contain different genetic mutations - which means treatments focused on only one target are ineffective or only partially effective.

"There have also been few new treatments over the past few decades for GBM, so it's clear that we need to find a way to make current treatments more effective for these patients," said the study's senior author Yi Fan, MD, PhD, an assistant professor of Radiation Oncology at Penn.

Since developing a treatment based on tumor mutations is difficult in GBM, this study took a different approach, focusing instead on overcoming resistance. Researchers found that GBM transforms a type of stromal cells called endothelial cells so that they act more like stem cells, which drives tumor resistance. They then went a step further and found the resistance is enabled by a signaling pathway known as Wnt. The more Wnt is activated, the more a cell is able to resist treatment like chemotherapy. Previous research has shown that GBM stimulates Wnt activity, meaning these new findings show the way in which these tumors co-opt their environment to survive attack.

These findings could also mean that blocking Wnt signaling may be an effective way to help these cells overcome resistance to treatment. Fan and his team used an experimental approach to shut off Wnt signaling in stromal cells in mice as well as tumor samples taken from human patients, and they found these cancer cells were vulnerable to chemotherapy once the signal was blocked.

Fan said this unique approach of using Wnt inhibitors to target stromal cells instead of the cancer cells themselves carries several benefits. First, stromal cells support the development of other cells, which in the case of GBM includes cancer. By targeting them, a treatment would effectively be getting closer to the root cause of why a tumor is able to survive and thrive in the first place, potentially making any such therapy more efficient. Second, not only does it show promise not in overcoming a tumor's initial resistance, it should also mean treatments will remain effective even as the tumor changes.

"Because stromal cells have a more stable genome, they will not mutate the way cancer cells do, meaning secondary resistance is unlikely," Fan said.

The team hopes to test this approach in a clinical trial.
This study was performed in cooperation with the Glioblastoma Translational Center of Excellence at the Abramson Cancer Center. Additional Penn authors include lead author Menggui Huang, as well as Duo Zhang, Janet Y. Wu, Kun Xing, Eujin Yeo, Chunsheng Li, Lin Zhang, Lutian Yao, Ling Qin, Zev A. Binder, Donald M. O'Rourke, Steven Brem, Constantinos Koumenis, and Yanqing Gong.

This study was supported by the National Institutes of Health (R01NS094533, R01NS106108), the American Association for Cancer Research Judah Folkman Award, and the McCabe Foundation Award of the University of Pennsylvania.

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $7.8 billion enterprise.

The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $425 million awarded in the 2018 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center--which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report--Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nation's first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Home Care and Hospice Services, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is powered by a talented and dedicated workforce of more than 40,000 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2018, Penn Medicine provided more than $525 million to benefit our community.

University of Pennsylvania School of Medicine

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