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.”
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.
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.