New Glioma Stem Cell-Related Target Identified for Potential Treatment of Glioblastoma

A Cleveland Clinic-led research team has defined a new mechanism that contributes to the lethality of glioblastoma. The findings, published recently in Science Translational Medicine, focus on glioma stem cells, a particularly dangerous subset of cancer cells that can self-renew and promote tumor growth and resistance to conventional therapies.

Previous research has shown that the SOX2 protein plays an important role in maintaining the disease-driving properties of glioma stem cells. In the new study, Shideng Bao, PhD, and collaborators discovered that another component, DNA-dependent protein kinase (DNA-PK), is also involved. According to their findings, DNA-PK critically controls the stability of SOX2 to maintain glioma stem cells in glioblastoma.

“Our preclinical findings indicate that DNA-PK is a promising new target for disrupting the pro-tumor properties of glioma stem cells to improve glioblastoma treatment,” says Dr. Bao, research staff in the Department of Cancer Biology in Cleveland Clinic’s Lerner Research Institute and Director of its Center for Cancer Stem Cell Research.

How DNA-PK maintains glioma stem cells to drive glioblastoma growth

The researchers found that DNA-PK actually modifies the SOX2 protein through phosphorylation, which stabilizes and prevents SOX2 degradation. It is this stable form of SOX2 that helps maintain the self-renewing and pro-tumor characteristics of glioma stem cells.

One of the defining characteristics of glioma stem cells is their resemblance to neural stem cells, Dr. Bao explains. Similar to neural stem cells, glioma stem cells are poorly differentiated or completely undifferentiated, giving them the capacity to self-replicate and to differentiate into a variety of specialized brain cells.

“These characteristics of glioma stem cells, along with their ability to invade normal brain tissue, make them major drivers of disease progression and therapeutic resistance,” Dr. Bao says. “Therefore, eliminating them or inducing their differentiation may improve therapeutic efficacy for glioblastoma.”

Notably, the researchers found that targeting DNA-PK promotes glioma stem cell differentiation, leading to inhibition of tumor growth and increased sensitivity to radiotherapy in mice.

Accelerating differentiation holds promise to slow disease

Radiation and chemotherapy agents such as etoposide and temozolomide work by damaging DNA in cancer cells. Dr. Bao’s team found that this DNA damage caused the DNA-PK/SOX2 protein complex to separate. As a result, the SOX2 protein degraded, helping to accelerate glioma stem cell differentiation. In other models, the researchers inhibited DNA-PK activity by its specific inhibitor or disrupted DNA-PK expression, which directly resulted in SOX2 degradation and glioma stem cell differentiation.

“We found that pharmacologically inhibiting DNA-PK potently promoted glioma stem cell differentiation, thereby preventing or reducing the cells’ capacity to self-replicate and suppressing glioma stem cell-driven tumor growth,” Dr. Bao notes. “Because glioma stem cells are much more resistant to radiation than differentiated glioma cells, targeting DNA-PK to induce glioma stem cell differentiation sensitized glioblastoma to radiation in preclinical models and improved the therapeutic efficacy.”

Given the beneficial effects in animal models, the researchers believe that targeting DNA-PK alone or in combination with other therapies, such as radiation, for treating glioblastoma is worthy of future investigation in clinical trials.

The research reported here was supported in part by the National Cancer Institute and the National Institute of Neurological Disorders and Stroke.