Glioblastoma (GBM) is one of the most aggressive brain cancers, presenting significant challenges due to its high mortality rate and resistance to treatment. In Brazil, an estimated 10,000 to 12,000 new cases emerge annually, although exact figures remain unavailable. This disease accounts for nearly half (49%) of all brain tumors, with most patients surviving only about 12 months after diagnosis.
Limitations of Traditional Treatment
Current treatment options for glioblastoma include surgery, chemotherapy, and radiotherapy. Temozolomide (TMZ), a chemotherapy drug approved in the late 1990s, remains the primary medication used to manage the disease. However, glioblastoma rarely responds completely to treatment, often recurring within months in a more aggressive and invasive form. Scientists have been working for years to identify new therapeutic targets to enhance patient survival and quality of life.
Investigating Tumor Stem Cells
Professor Marilene Hohmuth Lopes and her team at the Laboratory of Neurobiology and Stem Cells, Biomedical Sciences Institute of the University of São Paulo (ICB-USP), explored the mechanisms of tumor cells that persist in brain tissue even after extensive treatment. Their findings, published in BMC Cancer, highlight the crucial role of the prion protein in glioblastoma biology.
Surgery and temozolomide eliminate rapidly dividing tumor cells, but glioblastoma stem cells remain dormant in brain tissue. Over time, these cells reactivate, driving tumor regrowth. “Stem cells are powerful—they can self-renew, stay inactive for a while, and later regenerate an entire tumor,” explains Lopes. This resilience makes them key targets in glioblastoma research.
The Role of Prion Protein in Glioblastoma
Prion proteins, naturally produced by the human body, play essential roles in the central nervous system. They influence brain plasticity, cognitive processes like memory formation, and neuronal communication. Lopes had been studying prion proteins before discovering their link to aggressive tumors.
Her team found that patient samples from highly aggressive glioblastomas exhibited elevated levels of prion protein. This led them to investigate its impact on glioblastoma stem cells, which are responsible for tumor recurrence. Notably, prion proteins are located on the cell surface, making them viable drug targets. “Targeting a protein on the cell surface is much easier than one inside the cell, especially when crossing the blood-brain barrier,” Lopes explains.
CRISPR-Cas9 Genetic Editing to Suppress Prion Protein
As reported by medicalxpress, the researchers used CRISPR-Cas9 gene-editing technology to block prion protein production in glioblastoma stem cells. This significantly altered tumor cell behavior, reducing their ability to invade and proliferate. “This finding confirms that prion protein is a potential therapeutic target,” Lopes states. However, she cautions that a single protein is unlikely to drive tumor growth alone. The team continues to explore how prion proteins interact with other signaling pathways.
Exploring the Prion-CD44 Connection
Further investigation revealed a link between prion proteins and CD44, a well-known cancer stem cell marker that contributes to breast and colon cancer invasion. “We recently discovered that prion proteins and CD44 influence each other. Now, we’re working to understand this relationship better,” says Lopes.
The team suspects that prion proteins act as scaffolds, forming multiprotein signaling platforms that enable cancer cells to survive and proliferate. When researchers blocked prion protein production using CRISPR-Cas9, tumor cell self-renewal, migration, and invasion were significantly impaired.
Future Implications of the Study
While these findings are promising, Lopes emphasizes that clinical applications remain distant. “Basic research takes years to translate into treatments. We’re still working to understand how prion proteins regulate other genes involved in tumor growth and survival,” she explains. Nevertheless, the study represents an important step toward identifying new therapeutic strategies for glioblastoma.
The research continues, aiming to unravel the complex mechanisms behind glioblastoma recurrence and identify innovative treatment possibilities for one of the most challenging cancers in modern medicine.