Resume: Researchers 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.
Key Facts:
- The PI3K-beta signaling pathway is crucial for glioblastoma cell survival during chemotherapy.
- Blocking PI3K-beta increases the sensitivity of tumor cells to treatment with temozolomide.
- This discovery offers a potential new approach to treating glioblastoma by overcoming drug resistance.
Source: Virginia technology
For many patients with a deadly form of brain cancer called glioblastoma, resistance to chemotherapy is a major problem.
Current standard treatments, including surgery, radiation, and chemotherapy with the drug temozolomide, have limited effectiveness and have not changed significantly in the past fifty years. 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 the Fralin Biomedical Research Institute at VTC may be one step closer to a solution.
By working with glioblastoma cell cultures, including glioblastoma stem cells derived from patient samples, and laboratory mouse models harboring human cancer cells, scientists have discovered an effective molecular signaling pathway believed to be crucial for cancer cell survival during temozolomide treatment.
The findings are now online iSciencean open-access journal from Cell Publishing.
“Over the past 50 years, treatment options for glioblastoma have remained largely unchanged, relying on surgery, radiation 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 patients inevitably develop resistance to chemotherapy. Because it is the only currently available approved chemotherapy that can effectively reach the brain, finding ways to restore its effectiveness is crucial in addressing treatment failure in glioblastoma.”
Researchers investigated the molecular signaling pathway Phosphoinositide 3 Kinase (PI3K), which resembles a communication system in cells. It tells cells how to grow, survive and divide. When this pathway is activated, it can promote cancer growth. That’s why scientists and doctors generally thought that blocking it could be a way to treat cancer.
Their results have not been successful.
In the new study, scientists 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 the 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 treatment with temozolomide. In addition, using a drug that blocks PI3K beta, along with usual treatment, slowed the growth of the cancer cells.
Researchers aren’t sure why PI3K, in its different forms, is very similar in structure yet does different things in the body.
“The reason previous treatments targeting the PI3K pathway failed is because they did not distinguish between PI3K beta and the related proteins,” Sheng said. “This study shows that PI3K-beta is specific to glioblastoma, making it a crucial target for effective treatment.”
Going forward, overcoming the blood-brain barrier remains a hurdle to delivering P13K beta inhibitors to the brain, which will be crucial for translating the findings into the clinic to help patients.
“We will solve these problems in our future studies,” Sheng said.
Co-first authors of the study are Kevin Pridham, a former postdoctoral associate at the Fralin Biomedical Research Institute, and Kasen Hutchings and Patrick Beck, two former medical students at Virginia Tech Carilion School of Medicine who are continuing their medical careers in radiology. Las Vegas and pediatrics in Philadelphia, respectively.
Cell samples were provided by 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.
Financing: The research was supported by the National Institutes of Health.
About this brain cancer research news
Author: Johannes Pastoor
Source: Virginia technology
Contact: John Pastor-Virginia Tech
Image: The 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
Highlights
- Divergent roles of PI3K kinases in glioblastoma chemoresistance
- PI3Kβ surpasses PI3Kα/δ/γ in chemoresistance
- PI3Kβ inhibitors are effective chemosensitizers
- PI3Kβ regulates drug sensitivity in glioblastoma stem cells
Resume
Resistance to chemotherapy agents such as temozolomide is a major hurdle 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, non-selective blocking of PI3K kinases PI3Kα/β/δ/γ has produced undesirable clinical results. It is therefore imperative to investigate individual kinases in the chemosensitivity of glioblastomas.
Here we report that PI3K kinases were unevenly expressed in glioblastoma, with levels of PI3Kβ being the highest.
Patients deficient in O6-methylguanine-DNA methyltransferase (MGMT) and expressing elevated levels of PI3Kβ, defined as MGMT-deficient/PI3Kβ-high, responded less to temozolomide and experienced a poor prognosis. Consistently, MGMT-deficient/PI3Kβ-high glioblastoma cells were resistant to temozolomide.
Disruption of PI3Kβ, but not other kinases, sensitized MGMT-deficient/PI3Kβ-high glioblastoma cells or tumors to temozolomide. Furthermore, PI3Kβ-selective inhibitors and temozolomide synergistically reduced glioblastoma stem cell growth.
Our results demonstrated an essential role of PI3Kβ in chemoresistance, making PI3Kβ-selective blockade an effective chemosensitizer for glioblastoma.