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. This discovery offers a potential new approach to treating glioblastoma, a deadly brain cancer, by overcoming drug resistance and improving patient outcomes.
Highlights:
- The PI3K-beta signaling pathway is crucial for the survival of glioblastoma cells during chemotherapy.
- Blocking PI3K-beta increases the sensitivity of tumor cells to temozolomide treatment.
- This 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 therapy, and chemotherapy using temozolomide, have limited effectiveness and have not changed significantly over the past five decades. Although temozolomide may initially slow tumor progression in some patients, tumor cells usually quickly become resistant to the drug.
But now, Virginia Tech researchers at VTC’s Fralin Biomedical Research Institute may have taken a step closer to a solution.
Working with glioblastoma cell cultures, including glioblastoma stem cells derived from patient samples, and laboratory mouse models harboring human cancer cells, scientists have identified an effective molecular signaling pathway considered crucial for cancer cell survival during temozolomide treatment.
The results are now online at iSciencean open access journal from Cell Publishing.
“Over the past 50 years, treatment options for glioblastoma have remained largely unchanged, relying on surgery, radiation therapy and temozolomide,” said Zhi Sheng, senior author of the study and assistant professor at the Fralin Biomedical Research Institute.
“However, the effectiveness of temozolomide is limited and resistance to chemotherapy inevitably develops in patients. Since it is the only approved chemotherapy currently available that can effectively reach the brain, finding ways to restore its effectiveness is crucial to remedying glioblastoma treatment failure.
The researchers looked at the phosphoinositide 3 kinase (PI3K) molecular signaling pathway, which resembles 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 clinicians generally thought that blocking it might be a way to treat cancer.
Their results were not successful.
In this new research, scientists at the Fralin Biomedical Research Institute found that in some brain cancer patients who did not respond to treatment, levels were elevated of a specific form of signaling protein called PI3K-beta, which helps regulate cellular processes.
When they blocked only PI3K-beta in cell cultures and mouse models harboring cancer cells, the tumor cells became more sensitive to temozolomide treatment. Additionally, using a drug that blocks PI3K-beta in addition to usual treatment slowed the growth of cancer cells.
Researchers aren’t exactly sure why PI3Ks, in their different forms, are very similar in structure and yet have different effects in the body.
“The reason previous treatments targeting the PI3K pathway failed is because they did not distinguish between PI3K-beta and its related proteins,” Sheng said. “This research shows that PI3K-beta is specific to glioblastoma, making it the crucial target for effective treatment. »
In the future, overcoming the blood-brain barrier remains a barrier to delivering P13K-beta inhibitors into the brain, which will be crucial for translating the results into the clinic to help patients.
“We will resolve these issues in our future studies,” Sheng said.
The study’s co-first authors are Kevin Pridham, former postdoctoral associate at the Fralin Biomedical Research Institute, and Kasen Hutchings and Patrick Beck, two former Virginia Tech Carilion School of Medicine medical students who are continuing their medical careers in radiology in Las Vegas and Pediatrics in Philadelphia, respectively.
Cell samples were provided by the Carilion Clinic. The study results are based in part on data generated by the Cancer Genome Atlas research network, the Dependency Map, the Genotype-Tissue Expression or the Chinese Glioma Genome Atlas.
Funding: The research was supported by the National Institutes of Health.
About this brain cancer research news
Author: John Pasteur
Source: Virginia Tech
Contact: John Pastor–Virginia Tech
Picture: Image is credited to Neuroscience News
Original research: Free 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
Strong points
- Divergent roles of PI3K kinases in glioblastoma chemoresistance
- PI3Kβ outperforms PI3Kα/δ/γ in chemoresistance
- PI3Kβ inhibitors are effective chemosensitizers
- PI3Kβ regulates drug sensitivity in glioblastoma stem cells
Summary
Resistance to chemotherapies such as temozolomide poses a major obstacle to the effective treatment of treatment-resistant glioblastoma. This challenge arises from the activation of phosphatidylinositol 3-kinase (PI3K), making it an attractive therapeutic target.
However, nonselective blockade of PI3K kinases PI3Kα/β/δ/γ resulted in adverse clinical outcomes. It is therefore imperative to study individual kinases involved in glioblastoma chemosensitivity.
Here we report that PI3K kinases were unequally expressed in glioblastoma, with PI3Kβ levels being highest.
Patients deficient in O6-methylguanine-DNA-methyltransferase (MGMT) and expressing high levels of PI3Kβ, defined as deficient in MGMT/high PI3Kβ, were less sensitive to temozolomide and had a poor prognosis. Consistently, MGMT-deficient/high PI3Kβ glioblastoma cells were resistant to temozolomide.
Disruption of PI3Kβ, but not other kinases, glioblastoma cells or MGMT/PI3Kβ-deficient sensitized tumors elevated by temozolomide. Furthermore, selective PI3Kβ inhibitors and temozolomide synergistically attenuated the growth of glioblastoma stem cells.
Our results demonstrated the essential role of PI3Kβ in chemoresistance, making selective blockade of PI3Kβ an effective chemosensitizer for glioblastoma.