February 19, 2021
Inhibiting a key enzyme could help stop the growth of glioblastoma
Fewer than 10 per cent of people diagnosed with glioblastoma will survive beyond five years. Despite advances in understanding this deadly brain cancer, therapy options for this disease are severely limited. In a study recently published in Nature Communications, researchers have discovered that inhibiting a key enzyme, PRMT5, can suppress the growth of glioblastoma cells. Their findings demonstrate a novel approach to treating the disease, paving the way for a new class of therapeutics.
A multidisciplinary team with expertise in cancer stem cells, protein structures, small molecule development and multi-omic analyses enabled this discovery. The group, was co-led by Dr. Peter Dirks, Senior Scientist and Neurosurgeon at the Hospital for Sick Children (SickKids) and co-leader of OICR’s Brain Cancer Translational Research Initiative along with researchers at the Princess Margaret Cancer Centre, the Structural Genomics Consortium (SGC) and the University of Toronto. Many of the researchers involved in the study are also part of the Stand Up To Cancer (SU2C) Canada Cancer Stem Cell Dream Team, which receives support from OICR.
Through the study, they showed that inhibiting PRMT5 affected a large network of proteins that are important in cell division and growth, triggering cell senescence, and stopping the unrelenting division of cancer cells.
While PRMT5 inhibition has been previously suggested as a way to target brain and other cancers, no one has tested this strategy in a large cohort of patient tumour-derived cells that have stem cell characteristics, cells that are at the roots of glioblastoma growth.
They found that specific molecules – precursors to actual therapeutic drugs – inhibited the same enzyme, PRMT5, stopping the growth of a large portion of these patient-derived cancer stem cells. Many current drugs do not eliminate cancer stem cells, which may be why many cancers regrow after treatment.
“We used a different strategy to stop cancer cells from proliferating and seeding new tumours,” says co-senior author, Dr. Cheryl Arrowsmith, Senior Scientist at the Princess Margaret Cancer Centre who leads the University of Toronto site of the SGC. “By inhibiting one protein, PRMT5, we were able to affect a cascade of proteins involved in cell division and growth. The traditional way of stopping cell division has been to block one protein. This gives us a new premise for future development of novel, more precise therapies.”
“This strategy also has the opportunity to overcome the genetic variability seen in these tumours,” says co-senior author, Dirks, who also leads the SU2C Canada Dream Team. “By targeting processes involved in every patient tumour, which are also essential for the tumour stem cell survival, we side-step the challenges of individual patient tumour variability to finding potentially more broadly applicable therapies.”
The researchers also examined the molecular features of the patient-derived glioblastoma cells by comparing those that responded well to those that did not respond as well. They found a different molecular signature for the tumour cells that responded. In the future, this could lead to specific tumour biomarkers, which could help in identifying those patients who will respond best to this new class of drugs.
The research group will continue testing PRMT5 inhibitors to develop new therapies for people with glioblastoma.
“Right now, we have too few medicines to choose from to make precision medicine a reality for many patients,” says Arrowsmith. “We need basic research to better understand the mechanism of action of drugs, particularly in the context of patient samples. This is what will help us develop the right drugs to give to the right patients to treat their specific tumours.”
The research group also included OICR-affiliated scientists and staff researchers, Drs. Trevor Pugh, Mathieu Lupien, Benjamin Haibe-Kains, and Ahmed Aman.
Adapted from a SickKids news release.
June 9, 2020
OICR-supported study finds key mechanisms driving a severe form of brain cancer affecting infants and toddlers
When a young child is diagnosed with ependymoma, their treatment options are limited to surgery and radiation therapy – the latter of which causes severe side effects to the developing brain. Despite several clinical trials, scientists have yet to identify life-extending chemotherapies for this type of brain cancer.
In an OICR-supported study recently published in Cell, a research team at The Hospital for Sick Children (SickKids) re-examined how scientists have been studying ependymoma and invented new ways to model the disease. Their work has uncovered key mechanisms behind these tumours and new approaches to treat them.
Lead authors Dr. Antony Michealraj and Sachin Kumar, who are both members of Dr. Michael Taylor’s lab, discussed these promising findings with OICR News.
What spurred this research question?
AM: Unfortunately, treatment options for young children with ependymoma are very limited. Radiation treatments led to severe side effects and the disease often returns, so we are very motivated to develop new therapies for these infants and toddlers.
Our previous research showed that these brain tumours emerge very early in a child’s development and, remarkably, there are no specific genetic mutations that are known to cause these tumours. Instead, these tumours possess a unique way of regulating what genes are on or off – a unique epigenetic profile.
We observed that patient tumours have an enriched hypoxia (oxygen level) signature which is correlated with poor survival. These unusual scenarios pushed us to study how hypoxia and epigenetics are linked in ependymoma to search for potential solutions.
How did you approach this challenge and what did you find?
AM: The first problem that we faced was the availability of relevant disease models. What we realized was that we could not study the disease unless it was in a very specific environment with fine-tuned oxygen levels. In the body, these cancer cells only grow in low oxygen and we needed to mimic such an environment. Once we did so, we ended up with an exceptional experimental model of ependymoma that nobody has been able to create before.
These models allowed us to study the microenvironment of ependymoma cells. We saw that the cellular metabolism, or how a cell consumes and uses nutrients, was responsible for the epigenetic dysregulation seen in patients. Using an array of metabolic and epigenetic inhibitors, targeting these pathways destroyed ependymomas, providing an avenue for novel therapeutic interventions.
SK: One exciting finding was what we call our “Goldilocks” model. The key was histone lysine methylation – a process regulating how DNA is wrapped and coiled in a cell. Ependymoma cells require a very fine balance of histone lysine methylation, and too much or too little results in the cells dying.
By studying how to keep these cells alive, we learned how we could potentially eliminate them. The idea would be to find or repurpose drugs that target these pathways within the body, creating an unfavorable environment and eliminating them for good.
How can we translate these discoveries into new therapies for patients?
SK: With our new knowledge of the key molecular pathways involved in ependymoma, we can now look to develop specific compounds – or potential drugs – that can alter these pathways, disrupt the cancer cell’s environment, and prevent these tumours from growing. These compounds may include drugs that are already in clinical studies or completely new molecules. What’s great is that now we have a model that we can use to screen these drugs more effectively.
AM: We can screen FDA-approved drug libraries on these disease models which will enable us find potential chemotherapies rapidly. Since there are currently no approved medicines that work for this type of brain cancer, if we find a drug that works, it could potentially become the standard of care for this disease around the world.
We hope that these findings pave the way for future therapy development. Although we’re in the very early stages of developing any new drugs, we understand how important this work is to the children and families affected by the disease. We’re committed to finding new solutions for them.
Read more about our achievements in brain cancer research on OICR News.
May 25, 2020
OICR-funded researchers pinpoint short-lived cells that give rise to childhood brain tumours
Childhood brain tumours are remarkably complex, but understanding their origins could help researchers develop drugs to eliminate them. Where can these cells be found? How early do they appear? How do they lead to tumours? For Dr. Hayden Selvadurai, these unresolved questions were a call to action.
In a recent study, published in Cell Reports, Selvadurai and collaborators at The Hospital for Sick Children (SickKids) discovered a rare type of stem cell that gives rise to medulloblastoma, the most common type of brain cancer in children. Their study shows that these cells arise early in brain development and exist for a brief period of time – a developmental window which scientists can now home in on.
“If we can’t eliminate the stem cells at the root of medulloblastoma, we can’t effectively treat the disease,” says Selvadurai, who was a Postdoctoral Fellow under the supervision of Dr. Peter Dirks while leading this study. Dirks is Head of the Division of Neurosurgery at SickKids, Principal Investigator at The Arthur and Sonia Labatt Brain Tumour Research Centre, Professor at the University of Toronto and Co-leader of OICR’s Brain Cancer Translational Research Initiative (TRI). “These problematic cells arise amid a complex and intricate process of fetal brain development and we were able to pinpoint exactly when that happens.”
The study builds on the research group’s previous publication in Cancer Cell that traced the origins of medulloblastoma growth back to a small group of cells that distinctively expressed the SOX2 gene. Using single-cell RNA sequencing, lineage tracing and advanced imaging techniques, the team showed that these stem cells were responsible for generating all other tumour cells and could give rise to new tumours if not fully eliminated.
“I’m proud of these findings because we were able to unify our knowledge of developmental neurobiology with cancer biology,” says Selvadurai. “We were able to build on our understanding of medulloblastoma growth while improving our experimental models of brain cancer. Together, this work could help the community develop new effective treatments for patients with the disease.”
Dirks’ research group plans to further investigate the genes involved in the early stages of medulloblastoma in collaboration with OICR’s Brain Cancer TRI team.
This study was supported in part by the Canadian Institutes of Health Research and OICR through the Stand Up to Cancer (SU2C) Canada Cancer Stem Cell Dream Team.