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.
November 2, 2017
Biomarkers that can help predict a patient’s response to a given drug are central to testing new therapies in clinical trials as well as selecting which drugs to use in the clinic. Some of the biomarkers in use today rely on the overall expression of a given gene to predict if a drug will be of benefit. While these types of biomarkers have aided cancer research and treatment, a group led by Dr. Benjamin Haibe-Kains recently published research that is ushering in a new class of biomarkers – those based on gene isoforms (the different expression of the same gene within an individual). This work opens the door to more precise biomarkers.
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.
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.”
December 22, 2015
The first Stand Up to Cancer (SU2C) Canadian Dream Team of researchers was announced September 30, with $9 million provided over four years to support Canadian research on aggressive types of breast cancer.
The team, led by Dr. Tak Mak at the Princess Margaret Cancer Centre, will be developing new therapies aimed at changes in the genomes of cancer cells that make breast cancer tumours unstable and vulnerable to attack – the so-called “Achilles’ heel” of aggressive breast tumours. The researchers will test three candidate drugs and hope to identify biomarkers that will help to better personalize treatment for patients.