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 6, 2020
OICR-supported study helps move promising CAR-T cell therapy into a first-in-child clinical trial
Recurrent brain tumours are some of the most difficult cancers to treat, with no approved targeted therapies available and only a few potential therapies in clinical trials. Developing new drug treatments for these tumours is challenging in part because the drugs must overcome the blood-brain barrier and specifically target cancer cells while sparing the surrounding critical regions of the brain. Scientists at The Hospital for Sick Children (SickKids) have discovered a new solution.
In a study, recently published in Nature Medicine, a SickKids-led research team describes a novel treatment approach that delivers chimeric antigen receptor T (CAR-T) cell therapy directly into the cerebrospinal fluid that surrounds the tumour. Their findings show that the approach was effective in treating ependymoma and medulloblastoma, two common types of brain tumours, in experimental mouse models of human disease.
“The vast majority of children with recurrent metastatic medulloblastoma or ependymoma currently have a deadly prognosis, so it is very exciting to think we have identified a novel approach to treat this underserved patient population,” says senior author Dr. Michael Taylor, Neurosurgeon, Senior Scientist in the Developmental and Stem Cell Biology program and Garron Family Chair in Cancer Research at SickKids and Co-lead of OICR’s Brain Cancer Translational Research Initiative.
CAR-T cell therapies, which use genetically engineered immune cells to attack cancer cells, are remarkably effective in treating certain types of lymphomas and leukemias. Whereas CAR-T therapies are typically delivered through the blood stream, the research team discovered that delivering their engineered T cells directly into the cerebrospinal fluid provided a better chance for the therapy to reach and eliminate brain tumours.
The team performed in-depth molecular studies to design CAR-T cells that can recognize specific molecules on the surface of brain tumour cells. They also found that the use of a complementary approved cancer medication, azactyidine, boosts the efficacy of their approach.
Now, building on these findings, collaborators at Texas Children’s Hospital have launched a first-in-child clinical trial to test the safety and anti-tumour efficacy of their new strategy.
“This work was possible thanks to the concerted collaboration of our Pediatric Cancer Dream Team, which brought together scientists studying tumor genomics and tumor immunotherapy around the world to enable the design of more effective therapies for children with incurable and hard to treat cancers,” says corresponding author Dr. Nabil Ahmed, associate professor of pediatrics and immunology, section of hematology-oncology at Baylor and Texas Children’s Hospital.
This research was supported in part by OICR through OICR’s Brain Cancer Translational Research Intitiative and funding provided to the Stand Up to Cancer (SU2C) Canada Cancer Stem Cell Dream Team.
October 9, 2019
Change in just one letter of DNA code in a gene conserved through generations of evolution can cause multiple types of cancer
Toronto – (October 9, 2019) An Ontario-led research group has discovered a novel cancer-driving mutation in the vast non-coding regions of the human cancer genome, also known as the “dark matter” of human cancer DNA.
The mutation, as described in two related studies published in Nature on October 9, 2019, represents a new potential therapeutic target for several types of cancer including brain, liver and blood cancer. This target could be used to develop novel treatments for patients with these difficult-to-treat diseases.
“Non-coding DNA, which makes up 98 per cent of the genome, is notoriously difficult to study and is often overlooked since it does not code for proteins,” says Dr. Lincoln Stein, co-lead of the studies and Head of Adaptive Oncology at the Ontario Institute for Cancer Research (OICR). “By carefully analyzing these regions, we have discovered a change in one letter of the DNA code that can drive multiple types of cancer. In turn, we’ve found a new cancer mechanism that we can target to tackle the disease.”Continue reading – Researchers discover a new cancer-driving mutation in the “dark matter” of the cancer genome
May 1, 2019
Study identifies earliest traces of brain cancer long before the disease becomes symptomatic
Toronto (May 1, 2019) – Brain tumours are the leading cause of non-accidental death in children in Canada, but little is known about when these tumours form or how they develop. Researchers have recently identified the cells that are thought to give rise to certain brain tumours in children and discovered that these cells first appear in the embryonic stage of a mammal’s development – far earlier than they had expected.
“Progress in the development of more effective brain cancer treatments has been hampered in large part by the complex heterogeneity – or the variety of cells – within each tumour,” says Dr. Michael Taylor, Paediatric Neurosurgeon and Senior Scientist in Developmental and Stem Cell Biology at The Hospital for Sick Children (SickKids) and co-lead of the study. “We recognized that new technologies could allow us to unravel some of this complexity, so we combined our expertise with McGill and OICR to approach this problem together.”
Using mouse models, the research group investigated the different types of normal brain cells and how they developed at various timepoints in the cerebellum of the brain – the most common location for childhood brain tumours to appear. They mapped the lineages of over 30 types of cells and identified normal cells that would later transform into cancerous cells, also known as the cells of origin.
To pinpoint these specific cells, the group relied on single cell sequencing technology, which allows researchers to look at individual cells more clearly than traditional sequencing methods.
In their investigation, the cells of origin were observed much earlier in fetal development than one would expect, says Taylor, who is also a Professor in the Departments of Surgery and Laboratory Medicine and Pathology at the University of Toronto and Co-lead of OICR’s Brain Cancer Translational Research Initiative.
“Our data show that in some cases, these tumours arise from cell populations and events that would occur in humans at six weeks in utero,” says Dr. Lincoln Stein, Head of Adaptive Oncology at OICR and co-lead of the study. “This means that the brain tumours may be starting long before they show in clinic, even before a woman may know she is pregnant.”
“The brain is extraordinarily complex. These findings are not only important for better understanding brain tumours but they will also allow us to learn more about these cells and how they work, in order to help children with neurodevelopmental delays. What we have accomplished as a team in this study brings hope for patients,” adds Dr. Nada Jabado, Paediatric Hemato-Oncologist and Senior Scientist in the Child Health and Human Development Program at the Research Institute of the McGill University Health Centre and co-lead of the study. Dr. Jabado is also a professor of Pediatrics and Human genetics at McGill University.
“If we can understand where these tumours originate, we can better understand which cells to target and when to target them to create more effective and less toxic therapies for children,” says Ibrahim El-Hamamy, PhD candidate at OICR and co-first author of the study. “We’ve found new avenues and opportunities in a very complex disease and we look forward to actualizing this potential.”
With this knowledge, researchers can now study the differences between the development of normal, healthy cells and the cells that will eventually give rise to cancerous cells.Continue reading – The unanticipated early origins of childhood brain cancer
March 8, 2018
OICR’s Brain Cancer Translational Research Initiative (TRI) and the Terry Fox Precision Oncology for Young People Program (PROFYLE) are partnering to share data and deliver improved treatment options to young brain cancer patients.
September 6, 2017
Today’s therapies for medulloblastoma, a highly aggressive form of childhood brain cancer, bring benefits to young patients but also come with serious side effects. Dr. Michael Taylor and a team of international collaborators recently published results in Nature of an ambitious project that analyzed the genomes of around 500 cases of medulloblastoma. Their goal was to identify gene mutations that are commonly mutated in the cancer, but not in the normal cells of patients.
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.
November 1, 2016
Evaluating new therapies for cancer through clinical trials is one of the most important steps in moving novel drugs from the lab to clinical use. Recently Dr. Michael Taylor and his collaborators discovered a way to improve clinical trials for testing new therapies for medulloblastoma, a common form of brain cancer in children. The study was conducted with OICR’s support.
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.”