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UAB researchers identify potential therapeutic target against malignant brain tumors

UAB researchers identify potential therapeutic target against malignant brain tumors

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Researchers at the University of Alabama at Birmingham have identified a potential pathway to treating radiation-resistant glioblastoma, one of the most aggressive forms of brain cancer. The research, performed in animal models and human and mouse cells in culture, was published in the Journal of Clinical Investigation. The findings indicate that an adhesive cell surface protein known as N-cadherin — or N-cad — may be key in overcoming glioblastoma’s resistance to radiation therapy.

Even with the best surgery, radiation and chemotherapies, glioblastoma patients’ survival is less than two years on average. While radiation is a frequently used therapy to kill tumor cells, medical scientists have long known that in glioblastomas some tumor cells are resistant to radiation. Those surviving cells continue to reproduce and spread throughout the brain, leading to tumor regrowth.

The surviving tumor cells have stem cell-like properties, and are referred to as glioma stem cells (GSCs). They are innately less sensitive to radiation than the rest of the tumor. The UAB-led research team found that resistant GSCs are more adhesive and cluster together because they express increased levels of N-cad protein, which augments their resistance.

“Prior studies have revealed that radiation-resistant glioma cells behave like stem cells: They grow slowly but can multiply very efficiently, properties that contribute to resistance,” said Erwin Van Meir, professor in the Department of Neurosurgery, associate director of the O’Neal Comprehensive Cancer Center and the study’s senior author. “Currently, there are no effective therapies to target radiation-resistant GSCs, so deciphering the molecular pathways that underlie resistance is critical to develop new effective therapies for glioblastoma.”

“Our study reveals a major role for N-cad in establishing radiation resistance in mouse and human GSCs and further shows that lower N-cad levels correlate with glioblastoma patient survival,” said Dr. Satoru Osuka, assistant professor in the Department of Neurosurgery and first author of the paper. “Direct transfer of N-cad to sensitive GSCs made them resistant, and knockout of N-cad sensitized them to radiation, showing therapeutic potential. Altogether, these data indicate that N-cad is a driver of tumor resistance to radiation therapy, and provide proof-of-principle that targeting N-cad might sensitize the tumor to radiation, a major goal in oncology.”

There is another player at work, a glycoprotein called clusterin (CLU). CLU is normally secreted in response to stress and regulates cell survival, playing an important role in programmed cell-death signaling in cancer. It is overexpressed in several cancers, including malignant glioma.

“Our studies now reveal a new role for clusterin in GSC resistance, and establish a novel relationship between CLU and N-cad expression,” Van Meir said. “We found that N-cad is a strong inducer of CLU expression in GSCs, thereby inducing an anti-apoptotic state through elevation in CLU secretion. This innovative finding provides a new avenue for targeting the N-cad/CLU survival signaling axis to reduce radiation resistance in GBM.”

Clusterin inhibitors are being analyzed in clinical trials, and this study provides the rationale for testing them in glioblastoma in conjunction with radiation therapy to prevent the emergence of resistance.

Picropodophyllin (PPP) is an experimental cancer drug being investigated in clinical trials. Interfering with the receptors that cells use to connect and communicate can disrupt the effects of that communication.

This work was supported in part by grants from the National Institutes of Health, Department of Defense, Southeastern Brain Tumor Foundation and the Japan Society for the Promotion of Science.

Other authors from UAB are G. Yancey Gillespie, Dr. Chaoxi Li, Christian Stackhouse and Dr. Christopher Willey. Co-authors from Emory University are Dan Zhu, Zhaobin Zhang and Jeffrey Olson. Co-authors from Keio University, Tokyo, Japan, are Oltea Sampetrean and Hideyuki Saya.

This story originally appeared on the UAB News website.


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