Summary: Researchers have identified a key signaling pathway, PI3K-beta, responsible for chemotherapy resistance in glioblastoma. Blocking this pathway makes tumor cells more sensitive to temozolomide, a standard chemotherapy drug. The discovery offers a potential new approach to treating glioblastoma, a deadly brain cancer, by overcoming drug resistance and improving patient outcomes.
Key facts:
- The PI3K-beta signaling pathway is critical for glioblastoma cell survival during chemotherapy.
- Blocking PI3K-beta increases the sensitivity of tumor cells to temozolomide treatment.
- The discovery offers a potential new approach to treating glioblastoma by overcoming drug resistance.
Source: Virginia Tech
For many patients with a deadly type of brain cancer called glioblastoma, resistance to chemotherapy is a major problem.
Current standard treatments, including surgery, radiation and chemotherapy using the drug temozolomide, have limited efficacy and have not changed significantly over the past five decades. Although temozolomide can initially slow tumor progression in some patients, usually the tumor cells quickly become resistant to the drug.
But now, Virginia Tech researchers with the Fralin Biomedical Research Institute at VTC may have moved one step closer to a solution.
Working with glioblastoma cell cultures, including glioblastoma stem cells obtained from patient samples and laboratory mouse models containing human cancer cells, the researchers pinpointed an effective molecular signaling pathway believed to be critical for cancer cell survival during temozolomide treatment.
The findings are now online iScienceopen access journal of Cell Publishing.
“Over the past 50 years, treatment options for glioblastoma have remained largely unchanged, relying on surgery, radiation and temozolomide,” said Zhi Sheng, the study’s lead author and an assistant professor at the Fralin Biomedical Research Institute.
“However, the efficacy of temozolomide is limited and patients inevitably develop resistance to chemotherapy. As it is the only approved chemotherapy currently available that can effectively target the brain, finding ways to restore its effectiveness is critical to addressing treatment failure in glioblastoma.”
The researchers investigated the phosphoinositide 3 kinase (PI3K) molecular signaling pathway, which is like a communication system inside cells. It tells cells how to grow, survive and divide. When this pathway is activated, it can promote cancer growth, so scientists and doctors have generally thought that blocking it might be a way to treat cancer.
Their results were not successful.
In new research, researchers at the Fralin Biomedical Research Institute found that some brain cancer patients who did not respond to treatment had high levels of a specific form of a signaling protein called PI3K-beta, which helps regulate cellular processes.
When they blocked only PI3K-beta in cell cultures and mouse models containing cancer cells, the tumor cells became more sensitive to temozolomide treatment. In addition, using a drug that blocks PI3K-beta along with usual treatment slowed the growth of cancer cells.
Researchers aren’t sure why PI3K in its different forms are very similar in structure, but they do different things in the body.
“The reason previous treatments targeting the PI3K pathway failed is that they did not distinguish between PI3K-beta and related proteins,” Sheng said. “This research shows that PI3K-beta is specific to glioblastoma, making it a key target for effective treatment.”
Going forward, overcoming the blood-brain barrier remains an obstacle to delivering P13K-beta inhibitors to the brain, which will be key to translating the findings into the clinic to help patients.
“We will address these issues in our future studies,” Sheng said.
The study’s co-first authors are Kevin Pridham, a former postdoctoral fellow at the Fralin Biomedical Research Institute, and Kasen Hutchings and Patrick Beck, two former medical students at the Virginia Tech Carilion School of Medicine who are continuing their medical careers in Las Vegas radiology and pediatrics in Philadelphia, respectively
Cell samples were provided by Carilion Clinic. The study results are partially based on data generated by The Cancer Genome Atlas Research Network, Dependency Map, Genotype-Tissue Expression or Chinese Glioma Genome Atlas.
Funding: The research was supported by the State Health Institute.
About this brain cancer research news
Author: John Pastor
Source: Virginia Tech
Contact: John Pastor – Virginia Tech
Picture: Image is credited to Neuroscience News
Original Research: Open access.
“Selective regulation of chemosensitivity in glioblastoma by phosphatidylinositol 3-kinase beta” by Zhi Sheng et al. iScience
Abstract
Selective regulation of chemosensitivity in glioblastoma by phosphatidylinositol 3-kinase beta
Highlighting
- Divergent roles of PI3K kinases in glioblastoma chemoresistance
- PI3Kβ outperforms PI3Kα/δ/γ in chemoresistance
- PI3Kp inhibitors are potent chemosensitizers
- PI3Kp regulates drug sensitivity in glioblastoma stem cells
summary
Resistance to chemotherapies such as temozolomide is a major obstacle to the effective treatment of therapy-resistant glioblastoma. This challenge arises from the activation of phosphatidylinositol 3-kinase (PI3K), making it an attractive therapeutic target.
However, non-selective blocking of PI3K kinases PI3Kα/β/δ/γ produced undesirable clinical results. It is therefore necessary to investigate individual kinases in the chemosensitivity of glioblastoma.
Here, we report that PI3K kinases were unevenly expressed in glioblastoma, with PI3Kβ levels being the highest.
Patients with O6-methylguanine-DNA-methyltransferase (MGMT) deficiency and expressing elevated levels of PI3Kβ, defined as MGMT-deficient/PI3Kβ-high, responded less well to temozolomide and had a poor prognosis. Accordingly, MGMT/PI3Kp-high-deficient glioblastoma cells were resistant to temozolomide.
Perturbation of PI3Kβ, but not other kinases, sensitized glioblastoma cells or MGMT/PI3Kβ-deficient tumors to high temozolomide. In addition, PI3Kβ-selective inhibitors and temozolomide synergistically attenuated the growth of glioblastoma stem cells.
Our results demonstrated the essential role of PI3Kp in chemoresistance, making selective blockade of PI3Kp an effective chemosensitizer for glioblastoma.