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
July 17, 2019
Collaborative research group maps the three-dimensional genomic structure of glioblastoma and discovers a new therapeutic strategy to eliminate cells at the roots of these brain tumours
Current treatment for glioblastoma – the most common type of malignant brain cancer in adults – is often palliative, but new research approaches have pointed to new promising therapeutic strategies.
A collaborative study, recently published in Genome Research, has mapped the three-dimensional configuration of the genome in glioblastoma and discovered a new way to target glioblastoma stem cells – the self-renewing cells that are thought to be the root cause of tumour recurrence.
The research group integrated three-dimensional genome maps of glioblastoma with other chromatin and transcriptional datasets to describe the mechanisms regulating gene expression and detail the mechanisms that are specific to glioblastoma stem cells. They are one of the first groups in the world to perform three-dimensional genomic analyses in patient-derived tumour samples.
“The 3D configuration of the genome has garnered much attention over the last decade as a complex, dynamic and crucial feature of gene regulation,” says Dr. Mathieu Lupien, Senior Scientist at the Princess Margaret Cancer Centre, OICR Investigator and co-author of the study. “Looking at how the genome is folded and sets contacts between regions tens to thousands of kilobases apart allowed us to find a new way to potentially tackle glioblastoma.”
Through their study, the group discovered that CD276 – a gene which is normally involved with repressing immune responses – has a very important role in maintaining stem-cell-like properties in glioblastoma stem cells. Further, they showed that targeting CD276 may be an effective new strategy to kill cancer stem cells in these tumours.
Lupien adds that advancements in three-dimensional genomics can only be made through collaborative efforts, like this initiative, which was enabled by OICR through Stand Up 2 Cancer Canada Cancer Stem Cell Dream Team, OICR’s Brain Cancer Translational Research Initiative and other funding initiatives.
“This research was fueled by an impressive community of scientists in the area who are committed to finding new solutions for patients with brain cancer,” Lupien says. “Our findings have emphasized the significance of three-dimensional architectures in genomic studies and the need to further develop related methodologies to make sense of this intricacies.”
Senior author of the study, Dr. Marco Gallo will continue to investigate CD276 as a potential therapeutic target for glioblastoma. He plans to further delineate the architecture of these cancer stem cells to identify more new strategies to tackle brain tumours.
“A key problem with current glioblastoma treatments is that they mostly kill proliferating cells, whereas we know that glioblastoma stem cells are slow-cycling, or dormant. Markers like CD276 can potentially be targeted with immunotherapy approaches, which could be an effective way of killing cancer stem cells, irrespective of how slowly they proliferate,” says Gallo, who is an Assistant Professor at the University of Calgary. “Being able to kill cancer stem cells in glioblastoma could have strong implications for our ability to prevent relapses.”
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
April 17, 2019
Collaborative research group identifies new cancer-driving mechanisms in brain cancer stem cells, describes novel ways to overcome the limited effectiveness of standard therapy
Glioblastoma is the most common and the most deadly type of brain cancer found in adults, yet there have been no new advances in treating this disease for almost two decades. Recent research has provided a wealth of knowledge about the genomics – or the abnormal genetic code – of glioblastoma, but this has yet to translate into new treatments for patients. Understanding which genes drive glioblastoma can help uncover new ways to treat this incurable disease, and a pan-Canadian research group has set out to do just that.
Researchers from the University of Toronto, The Hospital for Sick Children and the University of Calgary have teamed up to identify genetic vulnerabilities in brain cancer stem cells – the cells that often resist treatment and cause the disease to return in patients after treatment. Their recent findings, which were published today in Cell Reports, uncovered new targets for glioblastoma and unraveled some of the complex mechanisms behind the disease.
“We set out to understand which genes are important functionally,” says Dr. Graham MacLeod, co-primary author of the study and Research Associate in the lab of Dr. Stéphane Angers at the University of Toronto. “Connecting a gene to its function is a bit like connecting circuits on a very complex circuit board. If we can understand which genes are important, then we can find hints into where to unplug, plug in, stop and start mechanisms so that we can potentially stop the progression of the disease.”
The group used CRISPR-Cas9 gene editing tools, which Angers and MacLeod specialize in, to investigate all 20,000 genes within the genome and identify the key genes that are required for glioblastoma cells to survive and grow. In their study, they identified one gene in particular whose function is already targeted in leukemia treatments. Angers says this is promising “because it uncovered a biological process, not previously suspected to be implicated in glioblastoma, for which a small molecule drug already exists.”
As part of OICR’s Brain Cancer Translational Research Initiative, the next stage of their research will use the same gene editing approach to investigate tumour cells after therapy to find the genes or the genomic changes that help tumour cells evade treatment and recur in patients.
Read more about this research on University of Toronto News or learn more about the Stand Up To Cancer 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.
July 31, 2018
OICR-funded drug discovery project’s unique ‘open science’ business model is accelerating the search for a solution to lethal pediatric brain cancers
Diffuse intrinsic pontine glioma (DIPG) is a lethal and inoperable brain cancer with a median survival of less than a year from diagnosis. Finding solutions to this disease is challenging due to its rarity, scientific complexity and its presentation in pediatric populations. An OICR-funded team of researchers, led by Dr. Aled Edwards from M4K Pharma, have developed new potential drug candidates for DIPG that they will test in animal models in the coming months. They’ve reached this milestone ahead of schedule, with fewer resources required than anticipated, by using an ‘open drug discovery’ approach – sharing their methods and data with the greater research community to streamline the drug discovery process.
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.
October 24, 2017
Brain tumours resulting from the spread of cancer from its primary location, known as brain metastases (BM), are the most common form of brain tumours in adults. A team of Ontario-based researchers recently identified two genes that seem to play a central role in BM in lung cancer patients – findings that could lead to improved biomarkers and treatments for BM.
In a study published in the journal Acta Neuropatologica, Mohini Singh and her collaborators focused on a class of cells they have termed Brain Metastases Initiating Cells (BMICs), which leave the primary site of cancer and migrate to the brain.
Singh, a biochemistry PhD candidate in the lab of Dr. Sheila Singh at McMaster University, explains the approach the team took to study these cells. “There was a lack of preclinical models that we could use to comprehensively study BMICs and understand the mechanisms behind them. To conduct our study we used brain metastases from lung cancer patients, which we cultured in conditions to enrich for BMICs, and then transplanted them into mice. This method allowed us to study BMICs within a living host, which provides a more accurate representation of the development of brain metastasis in humans.”
The researchers performed in vitro and in vivo RNA interference screens utilizing their unique BM models, and found two genes that were essential to the regulation of BMICs: SPOCK1 and TWIST2. “We discovered that SPOCK1 is a regulator of self-renewal in BMICs, playing a role in the initiation of lung tumours and their metastasis to the brain,” explains Singh. Furthermore, the results were clinically relevant. “Increased SPOCK1 expression was seen in lung cancer biopsies of patients with known brain metastases, and was correlated with poor survival.” Through protein-protein interaction mapping the researchers also identified new pathway interactors of the two genes that could be used as novel targets in treatment of BM in lung cancer patients.
“Identifying these two genes could be of great use in improving the treatment of lung cancer. In the future we could predict those patients who are most at risk of developing a brain metastasis and use drugs to target BMIC regulatory genes such as SPOCK1 and TWIST2 to destroy the initiating cells and to block the spread,” says Singh. “This would result in keeping the lung cancer locally controlled and therefore more treatable.”
OICR funding was used to establish this study with further significant funding coming from the Canadian Cancer Society and the Brain Canada Studentship.
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.
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.