UAB researchers find potential new pathway in treating radiation-resistant glioblastoma

Researchers at the University of Alabama in Birmingham have identified a new pathway that could treat radiation-resistant glioblastoma, one of the most aggressive forms of brain cancer. The research, conducted in animal and mouse and mouse cell models in culture, was published in the Journal of Clinical Investigation. The results show that an adhesive cell surface protein called N-cadherin -; or N-cad -; be important in overcoming glioblastoma resistance to radiation.

Glioblastoma is the most aggressive brain tumor. Even with the best surgery, radiation and chemotherapies, patient survival averages less than two years. Although radiation is a medicine often used to kill tumor cells, medical scientists have long known that in glioblastomas, some tumor cells are resistant to radiation. The surviving cells reproduce and spread throughout the brain, leading to tumor regeneration.

The remaining tumor cells have gas-like properties, and are known as glioma gas cells, or GSCs. They are internally 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 higher levels of N-cad protein, which contributes to their resistance.

Previous studies have shown that radiation-resistant glioma cells behave like gas cells, they grow slowly but can multiply very effectively, properties that contribute to stress. At present, there are no effective treatments to target radiation-resistant GSCs, so it is vital that the molecular pathways that underlie resistance to the development of new effective treatments for glioblastoma are compromised. “

Erwin G. Van Meir, Ph.D., Professor, Department of Neurururgery, Deputy Director, O’Neal Comprehensive Cancer Center and Lead Author of the Study

“Our study highlights a key role for N-cad in establishing radiation resistance in mouse and human GSCs and further demonstrates that lower N-cad levels are associated with the survival of glioblastoma patients,” said Satoru Osuka, MD, Ph.D., assistant professor in the Department of Neurururgery and first author of the paper. “By transferring N-cad directly to sensitive GSCs they resisted, and hitting N-cad exposed them to radiation, revealing therapeutic potential. Overall, these data reveal that N-cad is an anti-tumor driver to radiation therapy, and provides proof-of-principle that targeting N-cad could sensitize the tumor to radiation, a key goal in oncology. “

Another player also works, a glycoprotein called Clusterin, or CLU for short. CLU is usually kept secret in response to stress and regulates cell survival, playing an important role in anti-apoptosis (programmed cell death) symptoms in cancer. Many cancers are overweight, including malignant glioma.

“Our studies now reveal a new role for Clusterin in the GSC conflict, and establish a modern relationship between CLU and N-cad expression,” Van Meir said. “We found that N -cad is a strong stimulant of CLU expression in GSCs, thus promoting an anti-apoptotic state through an increase in CLU secretion. This innovative discovery provides a new avenue for targeting the N-cad / CLU survival signal axis to reduce radiation resistance in GBM. “

Clusterin inhibitors are now being studied in clinical trials, and this study provides the rationale for testing them in glioblastoma in conjunction with radiation therapy to prevent strife.

The team also found that an increase in N-cad was stimulated by radiation-induced IGF1 secretion. IGF1, or insulin-like growth factor 1, stimulates the growth of many cell types by binding to its cell surface receptor. The study shows that IGF1 is significantly involved in radiation stress through N-cad. Targeting IGF1 may be a way to reduce N-cad sensitivity.

Picropodophyllin, or PPP, is an experimental cancer drug that is being studied in several clinical trials. It is a permeable blood-brain-barrier blocker of the IGF1 receptor. Blocking the receptors that cells use to connect and communicate can disrupt the effect of that communication -; in this case, the ability of IGF1 to stimulate N-cad sensation.

“Clinical trials with an IGF1 receptor inhibitor such as PPP could lead to effective combination therapy for glioblastoma patients,” Van Meir said. “Previous trials using IGF1 receptor blockers in glioblastoma patients have shown safety; however, the trial was performed only in recurrent patients who did not receive radiation treatment. Our preclinical data are in mice demonstrates that the combination of IGF1 receptor inhibitor and radiation significantly counteracts TSC-derived Tumor radiation, providing the rationale for testing this combination in new clinical trials for glioblastoma patients . “

“Overall, our collaborative study deepens our understanding of variable radiation stress during recurrence in glioblastoma, and confirms the IGF1 / N-cad / CLU signal axis as a novel target for radio sensitivity, which has direct therapeutic relevance, “Osuka said.