A team of researchers at the Hospital for Sick Children (SickKids) in Toronto, have demonstrated a designer peptide targeting a protein-protein interaction that could become a treatment for glioblastoma. The discovery of a previously unknown target, reported today in the journal Nature Cancer, could provide a new method to treat this aggressive form of cancer.
Glioblastoma is known to be a fast-spreading cancer, as it spreads quickly from its central mass throughout the brain, which makes it difficult to treat. One of the most common treatments, the chemotherapy temozolomide, encounters resistance in roughly half of all patients, with less than one percent of these patients surviving ten years after initial diagnosis.
“By uncovering the role of a previously unknown protein-protein interaction in glioblastoma, we were able to develop a designer peptide which possesses robust therapeutic efficacy in treating all major types of glioblastoma in preclinical models,” said Xi Huang, a senior scientist in the developmental & stem cell biology program at SickKids. “This could form the basis of next generation glioblastoma therapy.”
Huang, along with colleague Weifan Dong a postdoc in the Huang lab, discovered in their research that two proteins EAG2 and Kvβ2 are both highly present in glioblastoma cells and also interact with healthy brain tissue that is met by cancerous cells.
“We examined these two proteins closely and found that when they interacted they created a potassium channel complex that is fundamental to the aggressive nature of the cancer,” said Dong. “What’s amazing is that this EAG2-Kvβ2 potassium channel complex appears to form only in glioblastoma cells, not healthy cells.”
Armed with the information that this interaction was unique to glioblastoma, Huang and other researchers began looking for ways to affect this interaction as a potential treatment approach. Their findings show that the EAG2-Kvβ2 interaction is necessary in order for neurons to communicate with glioblastoma cells, facilitating tumor growth, invasion, and chemoresistance. In preclinical models, the team’s designer peptide prevented the EAG2-Kvβ2 interaction from occurring, which slowed the growth of the cancer, preventing it from spreading to surrounding cells while also resulting in the death of glioblastoma cells across all glioblastoma subtypes.
“Even tumors that had developed resistance to temozolomide responded to the designer peptide,” Dong noted. “But we did not observe any side effects, likely due to the EAG2-Kvβ2 interaction only seeming to be present in cancerous cells.”
The research effort of Huang and team took eight years drawing on the breadth of research areas within SickKids including Lu-Yang Wang, senior scientist in the Neurosciences & Mental Health program; Roman Melnyk, senior scientist in the Molecular Medicine program and Co-Director of SPARC Drug Discovery: and Peter Dirks, senior scientist in the Developmental & Stem Cell Biology program.
Given the promise of the designer peptides to halt the newfound protein-protein interaction that helps drive glioblastoma development, the Industry Partnerships & Commercialization (IP&C) at SickKids has filed a Patent Cooperation Treaty application to protect the finding and also begin efforts for its commercialization. The Huang team is aiming to complete preclinical studies with an eye toward quickly moving the peptide into clinical trials.
“Our study has benefited tremendously from the vibrant research community at SickKids,” said Huang. “We are continuing to work closely with other scientists and industry partners to fully unlock the potential of the designer peptide and move our research from the lab into the hands of people who need it most.”
