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.
November 17, 2020
Dr. Brian Nieman takes a deep dive into the neurocognitive side effects of childhood leukemia treatment seeking new ways to improve the lives of survivors
Due to advances in the treatment of childhood acute lymphoblastic leukemia (ALL), more than 90 per cent of children diagnosed with the disease will live long and relatively healthy lives. However, there are still long-term neurocognitive side effects – or lasting effects – of treatment including attention, processing speed and motor coordination difficulties. Investigating these lasting effects at The Hospital for Sick Children (SickKids) is Dr. Brian Nieman, who is committed to further improving the lives of childhood leukemia survivors.
Recently published in Neuroimage: Clinical and Pediatric Research are two of Nieman’s latest studies on the neurocognitive impact of ALL treatment on growing children. In these studies, Nieman and collaborators discovered that many leukemia survivors have neurocognitive abilities that are comparable to other children but on average survivors are doing worse than their peers.
“We see that leukemia treatment has broad and lasting implications on the brain,” says Nieman, OICR Investigator and Senior Scientist at SickKids. “Determining when these key changes occur and which part of a child’s treatment is causative will be an important step in designing protective or rehabilitative strategies in the future.”
The study that was published in Neuroimage: Clinical was the first to investigate the impact of ALL treatment on the brains of survivors ages 8-18 using MRI. The study found extensive structural differences in the brain between survivors and their peers. The study published in Pediatric Research focused on quality of life measures, and identified the impact of leukemia treatment on IQ, behavioural measures, attention and cognitive abilities.
With this new knowledge and Nieman’s expertise in experimental mouse model imaging, he and collaborators are now investigating which chemotherapy drugs cause these lasting effects and when these developmental changes are occurring in a leukemia patient’s development. They strive to identify new strategies to protect and rehabilitate the developing child’s brain.
“Over the last few generations, we’ve seen childhood leukemia survival reach 90 per cent. Over the last few decades, we’ve seen a shift in practice that has allowed patients to experience fewer side effects. But these studies demonstrate that treatment isn’t ideal yet,” says Nieman. “The results that we’ve collected suggest that we could potentially help many leukemia patients and we’re committed to do so.”
September 16, 2020
Scientists discover mechanism of bone loss caused by acute lymphocytic leukemia, identify targeted therapy for children
OICR-supported research team discovers new pathway through which leukemia cells damage bone and a treatment that may protect children with leukemia from these effects
Due to remarkable progress in the treatment of pediatric leukemias with multi-drug chemotherapy, upwards of 85 per cent of children with the disease survive. One consequence of this success, is that more than a third of these patients suffer from in-bone fractures and pain during leukemia and for years following their treatment. In a recent study, Ontario researchers at the Hospital for Sick Children (SickKids) have discovered a process by which leukemia cells damage bone and discover that a targeted therapy may be able to prevent this damage.
In their study, published in Science Translational Medicine, the research group discovered that the bone degradation in leukemia patients is triggered by a protein called RANKL on the surface of the leukemic cells interacting with receptors called RANK on the surface of bone-degrading cells. The group showed that a drug, which is similar to one that is currently in clinical trials for other cancers, could specifically block this RANKL-RANK interaction and prevent further bone damage.
“A pan-Canadian study demonstrated that 15 per cent of children display bone fractures at the time they are diagnosed with acute lymphocytic leukemia, or ALL,” says lead author Dr. Jayne Danska, Senior Scientist in the Genetics & Genome Biology program at SickKids and Associate Chief, Faculty Development and Diversity at the SickKids Research Institute. “In addition, standard ALL chemotherapy protocols include corticosteroids which further damage the bone. Survivors of childhood ALL experience fractures and pain, and some cases are so severe that they require a hip replacement in their teenage years. We have discovered one mechanism that contributes to ALL-associated bone damage and a potential way to prevent it.”
To make these discoveries, first author of the study, Dr. Sujeetha Rajakumar, a postdoctoral fellow at SickKids, transplanted ALL cells from patient donors into experimental mouse models to examine the effect of leukemia cells on bone and how to disrupt the RANKL-RANK interaction. This so-called xenotransplantation method was pioneered by Dr. John Dick at the University Health Network’s Princess Margaret Cancer Centre.
Using these animal models, Danska’s group showed that treatment of the ALL-transplanted mice with a protein therapeutic that blocks the RANKL-RANK interaction prevented bone damage despite high number of leukemia cells in the bone compartments.
“There are clinical trials underway to test whether RANKL-RANK antagonists can prevent bone degradation in adults with metastatic prostate and breast cancers,” says Danska, who is also a Professor in the University of Toronto’s Faculty of Medicine. “The data we report in the human ALL transplant model is encouraging because the availability of clinical data with this class of drug can accelerate application of our discoveries to clinical trials in youth with ALL.”
“Children with leukemia sustain unbelievably rigorous and lengthy chemotherapy treatments,” says Danska. “We’re eager to bring our discoveries into clinical trials that may help minimize these painful and life-altering late effects of this disease.”
Danska and study collaborators Drs. Cynthia Guidos and Johann Hitzler of SickKids, and Drs. Mark Minden and John Dick of the Princess Margaret Cancer Centre are members of OICR’s Acute Leukemia Translational Research Initiative (TRI), which partially funded the study.
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.
February 25, 2020
Researchers discover that childhood brain cancer could be treated by blocking key cell-surface protein, pointing to a potential treatment approach with fewer toxic side effects
Chemotherapy for children with brain cancer is often toxic, leaving patients with serious life-long side effects but OICR-funded researchers have uncovered a new approach that may help.
In a study published in the Journal of Experimental Medicine, the Ontario-based research team discovered that blocking a specific protein on the surface of brain cancer cells can suppress the rampant growth of a tumour without harming the development of the brain.
The study focused on the protein CLIC1 in medulloblastoma, the most common type of childhood brain cancer. The group found that disrupting CLIC1 can halt medulloblastoma growth with very little effect on the developing brain in mice.
“Brain cancer is the leading cause of cancer-related death in children and young adults,” says Dr. Xi Huang, Scientist in the Developmental & Stem Cell Biology Program at The Hospital for Sick Children (SickKids) and senior author of the study. “We need new treatments to help these patients.”
We believe our findings are significant because ion channels have been successfully targeted to treat numerous human diseases.Michelle Francisco
CLIC1 belongs to a class of proteins called ion channels, which are important in the development of several other diseases like diabetes, epilepsy and high blood pressure. Many existing drugs and compounds act as ion channel modulators. The Huang Lab now has the high-throughput screening equipment to assess thousands of drug-like chemicals for those that can best block these ion channels.
“We believe our findings are significant because ion channels have been successfully targeted to treat numerous human diseases,” says Michelle Francisco, Research Project Coordinator in the Developmental & Stem Cell Biology Program at SickKids and first author of the study. “This helps pave the way between this discovery today and the impact it can have in the clinic.”
These findings build on Huang’s previous research on the potassium channel EAG2, which – like CLIC1 – is critical to medulloblastoma growth. In partnership with collaborators, Huang has shown that EAG2 could be blocked with an FDA-approved drug for schizophrenia to treat medulloblastoma in experimental mouse models and in a small patient study.
“We are fortunate to work with world-leading brain cancer researchers in Ontario,” Huang says, “We look forward to continuing our research to find new solutions for this devastating disease by targeting ion channels.”
This research was funded by OICR’s Brain Cancer Translational Research Initiative, SickKids Foundation, Arthur and Sonia Labatt Brain Tumour Research Centre, Garron Family Cancer Centre, b.r.a.i.n.child, Meagan’s Walk, Natural Sciences and Engineering Research Council (NSERC) Discovery Grant, U.S. Department of Defense (DoD) Peer Reviewed Cancer Research Program Career Development Award, Canadian Institute of Health Research (CIHR) Project Grants, and Sontag Foundation Distinguished Scientist Award to Xi Huang.
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
September 3, 2019
OICR is proud to welcome Dr. Parisa Shooshtari as an OICR Investigator.
Shooshtari specializes in developing computational, statistical and machine learning methods to understand the biological mechanisms underlying complex diseases, like cancer and autoimmune conditions. She is interested in uncovering how genes are dysregulated in complex diseases by integrating multiple data types and applying machine learning methods to analyze single-sell sequencing data.
Of her many achievements, Shooshtari developed a computational pipeline to uniformly process more than 800 epigenomic data samples from different international consortia. She then built and led a team that developed a web-interface and an interactive genome-browser to make the database publicly available to download and explore.
Shooshtari joins the OICR community with research experience from Yale University and the Broad Institute of MIT and Harvard. She also served as a Research Associate with the Centre for Computational Medicine at the Hospital for Sick Children (SickKids).
Shooshtari recently became an Assistant Professor in the Schulich School of Medicine and Dentistry at Western University, where she officially began her career as an independent researcher. Here, Shooshtari discusses her commitment to collaboration and her transition to professorship.
Your work spans multiple disease areas from autoimmune diseases to cancer, what do these diseases have in common? Is there a specific disease that you’re more interested in?
My work focuses on complex diseases, where instead of one gene causing the disease, there are sometimes tens or hundreds of genes working together to give rise to an ailment.
When it comes to complex diseases, we also know that there are multiple factors that we need to consider, including genetics, epigenetics and environmental factors. We live in an era where we have rich datasets with many different types of data. Each of these data types sheds light upon a different aspect of the disease mechanism, but we need to integrate these data types to gain a comprehensive understanding of how a complex disease works.
I develop computational methods for integrative analysis, so complex diseases are definitely the most interesting to me. I feel lucky to be a researcher at this time when I can help bring these data types together to understand mechanisms of diseases, which in turn will help inform treatment selection or help find new therapeutic strategies.
I am interested in applying our data integration methods to several complex diseases but I am currently working with a few Canadian groups to help better understand Diffuse Intrinsic Pontine Glioma (DIPG) – a type of fatal childhood brain cancer.
Your current collaborators include researchers from Yale, Harvard, MIT, SickKids and other leading organizations. How did you initiate and sustain these collaborations?
At the beginning of my research career, I would reach out to scientists who were working on interesting, challenging and cutting-edge problems. I enjoy working in collaborative environments because I believe the key to success in biomedical research is through collaborations between researchers from diverse backgrounds.
With the support of my collaborators, I’ve been able to learn and shift my focus from theoretical computational sciences to applications of data science in genetics of complex diseases. Now, sometimes collaborators approach me with their rich data, which I’m eager to help analyze.
With your new appointment, what are you looking forward to over the next few years?
I am eager to continue expanding my research program and working with new scientists on exciting cutting-edge problems in genetics and epigenetics of complex diseases. New technologies have revolutionized how we study diseases, and we are transitioning to a point where these new technologies are revolutionizing how we treat diseases. I am confident that we will have better ways of treating these diseases in the future using personalized medicine, and I want to help make that a reality.
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.
December 4, 2017
OICR launches groundbreaking Cancer Therapeutics Innovation Pipeline to drive cutting-edge therapies to the clinic
Ten new projects were selected in the pipeline’s inaugural funding round, highlighting Ontario’s strengths in collaboration and drug discovery.
Toronto (December 4, 2017) – The Ontario Institute for Cancer Research (OICR) today announced the Cancer Therapeutics Innovation Pipeline (CTIP) initiative and the first 10 projects selected in CTIP’s inaugural round of funding. CTIP aims to support the local translation of Ontario discoveries into therapies with the potential for improving the lives of cancer patients. The funding will create a new pipeline of promising drugs in development, and attract the partnerships and investment to the province necessary for further clinical development and testing.
“Ontario congratulates OICR on this innovative approach to driving the development of new cancer therapies,” says Reza Moridi, Ontario’s Minister of Research, Innovation and Science. “The Cancer Therapeutics Innovation Pipeline will help ensure that promising discoveries get the support they need to move from lab bench to commercialization, and get to patients faster.”
October 23, 2017
In this post, Monique Johnson shares how the Ontario Molecular Pathology Research Network’s (OMPRN) 2017 Pathology Matters Meeting provided her with new insights into the field and introduced her to Ontario’s molecular pathology community.