Researchers have discovered new potential treatment targets for glioblastoma, a deadly form of brain cancer. These targets emerged from a study looking for genetic weaknesses in cancer stem cells derived from patients, which reflect the diversity found in tumors.
A research team led by the University of Toronto has found new targets that might play a crucial role in effectively treating glioblastoma, a severe type of brain cancer. These targets were uncovered through a study focusing on genetic weaknesses in cancer stem cells taken from patients, showcasing the diversity that exists within tumors.
Glioblastoma is the most prevalent brain cancer among adults and is notoriously difficult to treat. This difficulty arises mainly because glioblastoma cancer stem cells, from which tumors develop, often resist therapy. The cancer stem cells that remain after treatment can generate new tumors that are unresponsive to additional treatments.
“The reason glioblastoma tumors have been able to evade treatment is their highly variable makeup, both within individual tumors and across different patients,” explained Graham MacLeod, a co-first author of the study and senior research associate at U of T’s Donnelly Centre for Cellular and Biomolecular Research. “Tumors can differ significantly from one person to another, and even within a single tumor, there are various cell types that have genetic differences.”
The study was recently published in the journal Cancer Research.
A significant discovery from this research is that the variability among glioblastoma cancer stem cells can be categorized along a spectrum between two cell subtypes. On one end is the developmental subtype, resembling cells that have developed abnormally during neurodevelopment, while the other end represents the injury-response subtype, associated with inflammation. The study aimed to find treatment methods that specifically target each subtype, allowing for a more comprehensive approach to combatting tumors.
This investigation follows previous research published in Cell Reports, which identified weaknesses in glioblastoma cancer stem cells that affect their response to chemotherapy. The subsequent step was to examine how these vulnerabilities differ across a broad and varied collection of patient-derived cell lines in order to pinpoint the most common issues in each subtype.
The team conducted CRISPR/Cas9 screenings in glioblastoma stem cell lines originating from 30 patients, making this the largest study of its kind. The patient-derived cell lines were created by the lab of Peter Dirks, a professor of surgery and molecular genetics and Chief of the Division of Neurosurgery at SickKids. Within these cancer stem cell samples, the researchers identified genes that promote the growth of the two cell subtypes, which could be targeted to inhibit tumor development. By combining treatments to target both cell subtypes at once, they could create a more effective glioblastoma therapy.
“Much of the glioblastoma research relies on a limited number of immortalized cell lines maintained in serum, which are not ideal as they don’t accurately represent true glioblastoma cells,” said Fatemeh Molaei, co-first author of the study and a graduate student at the Donnelly Centre and the Leslie Dan Faculty of Pharmacy. “Our findings offer a more accurate reflection of a patient’s tumor because our cell lines are directly derived from a diverse group of patients. It was through screening these cell lines that we identified the OLIG2 and MEK genes as potential drug targets for the developmental subtype, as well as the FAK and B1-Integrin genes for the injury-response subtype.”
“Although it’s known that there are various subtypes of glioblastoma stem cells, these distinctions are often overlooked in clinical settings,” remarked Stéphane Angers, lead investigator of the study and director of the Donnelly Centre.
“In the future, our findings may aid in the development of new treatments tailored to individual patients by targeting the dominant cell subtype, or both subtypes simultaneously,” added Angers, who is also a professor in the Leslie Dan Faculty of Pharmacy and U of T’s Temerty Faculty of Medicine. “The capacity of glioblastoma to adjust to treatment is both its greatest strength and our most significant challenge. Our study enhances our knowledge of this cancer type and suggests a new treatment strategy that we hope will improve patient outcomes.”
This research received support from the Canadian Institutes of Health Research.
