Discovery of protein-protein interaction lays foundation for future glioblastoma therapy

Posted on September 11, 2023

Summary:

SickKids scientists present a novel approach to treat glioblastoma based on a newly discovered protein-protein interaction.

A fluorescent image of glioblastoma cells (green) scattered among healthy brain tissue (blue).

The discovery of a previously unknown molecular target has inspired what may become a therapeutic breakthrough for people with glioblastoma, the most common and aggressive brain cancer.

When people hear the word “cancer” they often picture a single mass, but glioblastoma cells are also highly invasive and spread quickly from the central mass, making it very difficult to fully eradicate. Even with current treatments such as temozolomide, the standard chemotherapy approved to treat glioblastoma, temozolomide-resistant tumours recur in more than 50 per cent of patients with less than one per cent surviving ten years after diagnosis.

In a study published in Nature Cancer, a research team at The Hospital for Sick Children (SickKids) showcased a new potential treatment approach for glioblastoma called a designer peptide, which targets a protein-protein interaction in the glioblastoma cells.

“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,” says Dr. Xi Huang, a Senior Scientist in the Developmental & Stem Cell Biology program. “This could form the basis of next generation glioblastoma therapy.”

[Music]

[The screen pans across an illustration of three individuals working in a lab.]

Text on screen: At The Hospital for Sick Children in Toronto, Canada, a research team led by Dr. Xi Huang has invented a designer peptide that may change the course of care for glioblastoma patients.

Text on screen: Glioblastoma is the most common and deadly brain cancer, and because of its complexity there have been no effective targeted therapies for decades.

[The screen transitions to an illustration of a side view of the brain with an orange mass located in the frontal lobe.]

[The screen zooms into the orange mass at a microscopic level, showing a group of glioblastoma cells.]

[The screen zooms into one of the glioblastoma cells amidst a group of neurons.]

Text on screen: By beginning their research inside the glioblastoma cells, the team identified two proteins that were highly expressed.

[The screen zooms into the interior of the glioblastoma cell. There are two distinct shapes in the cell: hexagons (blue) and squares (green), both with an extension on one of their sides that allows the shapes to conjoin. The two shapes float toward each other and connect together like puzzle pieces.]

[The new shape, consisting of the connected hexagon and square shapes, floats toward the edge of the cell and embeds itself in the cell membrane to create a channel. Small circles (purple) labelled "K+" in the cell are ejected through the channel.]

Text on screen: When the two proteins met, they created a potassium channel complex

[The screen transitions to a close-up of an end of a neuron next to a glioblastoma cell. Glowing yellow circles travel through the end of the neuron to the glioblastoma cell, which lights up yellow.]

Text on screen: that allowed the cancer cells to receive signals from nearby neurons, making cancer cells divide more frequently, become more invasive and resist chemotherapy.

[The screen transitions to the interior of the glioblastoma cell. Inside the cell, there is a circular shape (yellow) with an extension. The shape is circled and labelled "Designer peptide".]

Text on screen: To stop this interaction, Dr. Xi Huang and his team invented a designer peptide

[The green square and blue hexagon shapes float toward the designer peptide. The green square connects with the designer peptide before it gets the chance to connect with the blue hexagon. The blue hexagon bumps into the conjoined green square and designer peptide and floats out of the screen.]

Text on screen: that acts as a barrier between the two proteins.

[The conjoined green square and designer peptide bump against the cell membrane and float out of the screen.]

Text on screen: In multiple preclinical models, this designer peptide prevented the potassium channel complex from forming.

[The screen transitions to the close-up of an end of neuron next to a glioblastoma cell from before. There are no glowing yellow circles travelling down the neuron. The glioblastoma cell fails to light up yellow as it did previously.]

Text on screen: As a result, the glioblastoma cells could not effectively receive neuronal signal

[The screen transitions to an illustration of a group of glioblastoma cells. The glioblastoma cell in the centre is surrounded by neurons. The outline of the cell wavers before the cell bursts and disappears.]

Text on screen: and were destroyed, even in chemotherapy-resistant glioblastoma.

Text on screen: Since the protein-protein interaction appears to only occur in glioblastoma cells, no overt side effects were detected on surrounding brain cells.

[The background behind the text shows a faded illustration of the individuals working in the lab from the beginning of the video.]

Text on screen: Now, the research team is working to transform this breakthrough into a new therapy for people with glioblastoma.

[The screens fades to white.]

Text on screen: Visit sickkids.ca/designerpeptide to learn more.

Text on screen: Weifan Dong et al. (2023) "A designer peptide against the EAG2-Kvβ2 potassium channel targets the interaction of cancer cells and neurons to treat glioblastoma." Nature Cancer.

[The SickKids Research Institute logo sits under the title of the publication.]

Protein-protein interaction holds key to glioblastoma aggression

The development of the designer peptide began when Huang and first author Dr. Weifan Dong discovered that two proteins called EAG2 and Kvβ2, both highly present in glioblastoma cells, were interacting where cancerous cells meet with healthy brain tissue.

“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,” says Dong, a former PhD student and current postdoctoral fellow in the Huang Lab. “What’s amazing is that this EAG2-Kvβ2 potassium channel complex appears to form only in glioblastoma cells, not healthy cells.”

Excited by their findings, Huang’s team began investigating this specific interaction as a potential target for glioblastoma treatment. They determined that EAG2-Kvβ2 interaction is required for neurons to communicate with glioblastoma cells, facilitating tumour growth, invasion and chemoresistance. The designer peptide prevents the protein-protein interaction from occurring, slowing growth and deterring the cancer from spreading into surrounding cells. In preclinical models, the designer peptide also resulted in the death of glioblastoma cells across all subtypes of glioblastoma.

“Even tumours that had developed resistance to temozolomide responded to the designer peptide,” says Dong. “But we did not observe any side effects, likely due to the EAG2-Kvβ2 interaction only seeming to be present in cancerous cells”.

Building a next-generation treatment

Dr. Xi Huang

Over the course of the eight-year study the research team garnered important insights and support from leaders across the SickKids community, from Dr. Lu-Yang Wang, Senior Scientist in the Neurosciences & Mental Health program, to Dr. Roman Melnyk, Senior Scientist in the Molecular Medicine program and Co-Director of SPARC Drug Discovery, and Dr. Peter Dirks, Senior Scientist in the Developmental & Stem Cell Biology program.

Now, with the support of Industry Partnerships & Commercialization (IP&C) at SickKids, Huang’s designer peptide discovery has been protected by the filing of a Patent Cooperation Treaty (PCT) application, while active commercialization efforts led by IP&C are underway. Together, the team plans to complete preclinical studies and advance this designer peptide into clinical trials as soon as possible.

“Our study has benefited tremendously from the vibrant research community at SickKids,” says Huang, who also holds Canada Research Chair in Cancer Biophysics. “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.”

This research was funded by SickKids Foundation, the Canadian Cancer Society, Concern Foundation, b.r.a.i.n.child, Canadian Institutes of Health Research (CIHR), National Sciences and Engineering Research Council (NSERC), Sontag Foundation, Meagan’s HUG, Ontario Institute for Cancer Research, Ontario Ministry of Research, Innovation and Science, Arthur and Sonia Labatt Brain Tumour Research Centre, Garron Family Cancer Centre.