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.
January 4, 2021
Researchers discover brain cancer may develop when tissue healing runs amok, uncovering new approaches to combat the deadly disease
The healing process that follows a brain injury, such as an infection or a stroke, could spur tumour growth when the new cells generated are derailed by mutations, Toronto scientists have found. This discovery could lead to new therapy for glioblastoma patients who currently have limited treatment options with an average lifespan of 15 months after diagnosis.
The findings, published today in Nature Cancer, were made by an interdisciplinary team of researchers from OICR, the University of Toronto’s Donnelly Centre for Cellular and Biomolecular Research, The Hospital for Sick Children (SickKids) and the Princess Margaret Cancer Centre who are also on the pan-Canadian Stand Up to Cancer (SU2C) Canada Dream Team that focuses on a common brain cancer known as glioblastoma.
“Our data suggest that the right mutational change in particular cells in the brain could be modified by injury to give rise to a tumour,” says Dr. Peter Dirks, senior author of the study, OICR-supported researcher, Dream Team co-leader, and Head of the Division of Neurosurgery and a Senior Scientist in the Developmental and Stem Cell Biology program at SickKids. “We’re excited about what this tells us about how cancer originates and grows and it opens up entirely new ideas about treatment by focusing on the injury and inflammation response.”
The research group, led in part by OICR and Princess Margaret’s Dr. Trevor Pugh, applied the latest single-cell RNA sequencing and machine learning technologies to map the molecular make-up of the glioblastoma stem cells (GSCs), which Dirks’ team previously showed are responsible for tumour initiation and recurrence after treatment.
Equipped with these single-cell analysis methods, the research group was able to accurately differentiate and study different types of tumour cells. Through analyzing 26 tumours and nearly 70,000 cells, they found new subpopulations of GSCs that bear the molecular hallmarks of inflammation.
This finding suggests that some glioblastomas may start to form when the normal tissue healing process is derailed by mutations, possibly even many years before patients become symptomatic, Dirks says. Once a mutant cell becomes engaged in wound healing, it cannot stop multiplying because the normal controls are broken and this spurs tumour growth, according to the study.
The study’s authors, including co-leading researcher, Dr. Gary Bader from the Donnelly Centre as well as graduate students including Owen Whitley and Laura Richards, are now working to develop tailored therapies target these different molecular subgroups.
“There’s a real opportunity here for precision medicine.” says Pugh, who is Director of Genomics at OICR and the Princess Margaret Cancer Centre. “To dissect patients’ tumours at the single cell level and design a drug cocktail that can take out more than one cancer stem cell subclone at the same time.”
In addition to funding from the Stand Up To Cancer Canada Cancer Stem Cell Dream Team: Targeting Brain Tumour Stem Cell Epigenetic and Molecular Networks, the research was also funded by Genome Canada, the Canadian Institutes for Health Research, the Ontario Institute for Cancer Research, Terry Fox Research Institute, the Canadian Cancer Society and SickKids Foundation.
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.
October 24, 2018
Brain tumour tissue is often stiffer than normal tissue. New research funded by OICR helps to explain how this occurs – and how this knowledge can be used to help slow tumour development.
Uncontrolled cell growth in solid tumours, such as brain tumours, causes tumour tissue to be stiffer than healthy tissue, creating an advantageous environment for tumour cells to proliferate rapidly, avoid cell death and develop resistance to drugs. But how tumour tissue stiffens is not well understood. A research group based at the The Hospital for Sick Children (SickKids) recently discovered how tumour cells sense and respond to tissue rigidity. Their findings, recently published in Neuron, show that stopping the mechanism that drives tumour stiffness could slow cancer growth.
August 30, 2017
An international team of scientists have used an innovative barcode-like system to track the behaviour of individual glioblastoma cells, allowing them to see how the cells of this deadly form of brain cancer have successfully evaded treatment and how they spread.
July 11, 2017
New research group aims to exploit genomic differences within brain cancer to develop new treatments
This year, almost 3,000 Canadians will be diagnosed with brain cancer – one of the hardest forms of cancer to treat. In May, OICR launched its Brain Cancer Translational Research Initiative (TRI) to leverage recent insights into the genomic heterogeneity in two common types of brain cancer – Medulloblastoma (MB) and Glioblastoma Multiforme (GBM). Developing a better understanding of the genes and pathways central to MB and GBM will enable the development of new drugs and provide a much needed improvement in treatment options for patients, many of whom are children and young adults and are particularly susceptible to long-term side effects from treatment.
May 25, 2017
OICR launches five all-star teams of Ontario scientists to tackle some of the deadliest forms of cancer
Great strides have been made in cancer research, but much work remains to develop better treatments for the most lethal cancers and to advance new anti-cancer technologies. OICR is taking on a new approach, building on the success of the Institute’s first ten years and Ontario’s strength in particular cancer research areas. Reza Moridi, Ontario’s Minister of Research, Innovation and Science announced that the Institute is funding five collaborative, cross-disciplinary and inter-institutional Translational Research Initiatives (TRIs) with a total of $24 million over the next two years.
The TRIs will bring together some of the top cancer researchers in Ontario and be led by internationally renowned Ontario scientists. Each team will focus on a certain type of cancer or therapeutic technology. To maximize the positive impact of research on patients, the TRIs all incorporate clinical trials into their design. The TRIs, which were selected by an International Scientific Review Panel, are:
- Acute Leukemia TRI (led by Drs. John Dick and Aaron Schimmer at the University Health Network (UHN))
- Brain Cancer TRI (led by Drs. Peter Dirks and Michael Taylor at SickKids)
- Immuno-oncology TRI (ACTION) (led by Drs. John Bell and Marcus Butler at The Ottawa Hospital and UHN)
- Ovarian Cancer TRI (led by Drs. Amit Oza and Rob Rottapel at UHN)
- Pancreatic Cancer TRI (PanCuRx) (led by Dr. Steven Gallinger at UHN)
The funding will also support Early Prostate Cancer Developmental Projects led by Drs. Paul Boutros and George Rodriguez.
“In just over 10 years, the Ontario Institute for Cancer Research has become a global centre of excellence that is moving the province to the forefront of discovery and innovation in cancer research. It is home to outstanding Ontario scientists, who are working together to ease the burden of cancer in our province and around the world,” said Moridi.
“Collaboration and translational research are key to seeing that the innovative technologies being developed in Ontario reach the clinic and help patients,” said Mr. Peter Goodhand, President of OICR. “These TRIs represent a unique and significant opportunity to impact clinical cancer care in the province.”
— SickKids_TheHospital (@SickKidsNews) May 25, 2017
— UHN (@UHN_News) May 25, 2017
— The Ottawa Hospital (@OttawaHospital) May 25, 2017
May 25, 2017
OICR launches five large-scale Ontario research initiatives to combat some of the most deadly cancers
Toronto (May 25, 2017) – Reza Moridi, Ontario’s Minister of Research, Innovation and Science, today announced the Ontario Institute for Cancer Research is launching five unique, cross-disciplinary, multi-institutional Translational Research Initiatives (TRIs), each focused on a single type of or treatment approach to cancer. With $24 million in funding over two years, the TRIs will bring together world-leading scientists to tackle some of the most difficult to treat cancers and test innovative solutions to some of the most serious challenges in cancer today.
The TRIs build on Ontario’s proven strengths in areas such as stem cells, immuno-oncology, pediatric cancers, genomics, clinical trials and informatics. Working together, the province’s top scientists and clinicians will accelerate the development of much needed solutions for patients around the globe, with a focus on acute leukemia and brain, ovarian and pancreatic cancers. Each TRI includes clinical trials to maximize patient impact.
February 4, 2016
Stand Up To Cancer Canada Announces New Cancer Stem Cell Dream Team To Attack Brain Cancer in Children and Adults
Pan-Canadian Team of Researchers Will Receive CA $11.7 Million in Funding from Stand Up To Cancer Canada, Genome Canada, Canadian Institutes of Health Research, Cancer Stem Cell Consortium, and Ontario Institute for Cancer Research
February, 4, 2016—TORONTO—A team of top Canadian scientists, including leading pioneers of stem cell research, was named today to lead a new attack on brain cancers in children and adults, using genomic and molecular profiling technologies to focus on the cancer stem cells that drive the growth of tumours.
“Brain tumours are not as common as many other forms of cancer, but they are devastating, especially when they strike the very young,” said Phillip A. Sharp, PhD, Nobel laureate and institute professor at the Massachusetts Institute of Technology’s David H. Koch Institute for Integrative Cancer Research and co-chair of the Stand Up To Cancer (SU2C) Canada Scientific Advisory Committee (SAC). “The Dream Team will bring new insights to brain cancer research, which has been an underfunded area.”