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.”
The research group discovered that the mutation, termed the U1-snRNA mutation, could disrupt normal RNA splicing and thereby alter the transcription of cancer-driving genes. These molecular mechanisms represent new ways to treat cancers carrying the mutation. One of the potential treatment approaches includes repurposing existing drugs, which, by bypassing early drug development stages, could be brought into the clinic at an accelerated rate.
“Our unexpected discovery uncovered an entirely new way to target these cancers that are tremendously difficult to treat and have high mortality rates,” says Dr. Michael Taylor, Paediatric Neurosurgeon, Senior Scientist in Developmental and Stem Cell Biology and Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children (SickKids) and co-lead of the studies. “We’ve found that with one ‘typo’ in the DNA code, the resultant cancers have hundreds of mutant proteins that we might be able to target using currently available immunotherapies.”
The U1-snRNA mutation was found in patient tumours with certain subtypes of brain cancer, including nearly all of the studied samples from adult patients with sonic hedgehog medulloblastoma. The mutation was also found in samples of chronic lymphocytic leukemia (CLL) – the most common type of adult leukemia – and hepatocellular carcinoma – the most common type of liver cancer.
“This discovery is an example of how OICR is working together with partners in Ontario and across the world to support cutting-edge research that can be used in the development of precision therapies for cancer patients worldwide,” says Dr. Laszlo Radvanyi, President and Scientific Director of OICR.
The two related publications – one which focused on brain cancer and the other on CLL and liver cancer – were both led by researchers in Ontario, including Dr. Michael Taylor, who is also a Professor in the Departments of Surgery and Laboratory Medicine and Pathobiology at the University of Toronto, and Dr. Lincoln Stein at OICR. Both of the studies involved international collaborators including Dr. Xose Puente at the University of Oviedo, Dr. Elias Campo at the Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS) and the Universitat de Barcelona and others.
The studies were powered in part by data from the OICR-led Pan-Cancer Analysis of Whole Genomes (PCAWG) project, one of the largest coordinated cancer research endeavors to date that analyzed more than 2,800 cancer whole genomes from the International Cancer Genome Consortium (ICGC).
This research was supported in part by a Translational Research Initiative grant from OICR through funding provided by the Government of Ontario. This work was also funded in part by Genome Canada and SickKids Foundation.
About the Ontario Institute for Cancer Research (OICR)
OICR is a collaborative, not-for-profit research institute funded by the Government of Ontario. We conduct and enable high-impact translational cancer research to accelerate the development of discoveries for patients around the world while maximizing the economic benefit of this research for the people of Ontario. For more information visit www.oicr.on.ca.
About The Hospital for Sick
The Hospital for Sick Children (SickKids) is recognized as one of the world’s foremost paediatric health-care institutions and is Canada’s leading centre dedicated to advancing children’s health through the integration of patient care, research and education. Founded in 1875 and affiliated with the University of Toronto, SickKids is one of Canada’s most research-intensive hospitals and has generated discoveries that have helped children globally. Its mission is to provide the best in complex and specialized family-centred care; pioneer scientific and clinical advancements; share expertise; foster an academic environment that nurtures health-care professionals; and champion an accessible, comprehensive and sustainable child health system. SickKids is a founding member of Kids Health Alliance, a network of partners working to create a high quality, consistent and coordinated approach to paediatric health care that is centred around children, youth and their families. SickKids is proud of its vision for Healthier Children. A Better World.
Ontario Institute for Cancer Research
The Hospital for Sick Children (SickKids)
416-813-7654 ext. 201436
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.”
August 16, 2018
Ottawa researchers discover a new way to make cancer cells more susceptible to virus-based therapies
Over the past decade, researchers have made significant progress in designing oncolytic viruses (OVs) – viruses that destroy cancer cells while leaving healthy tissue unharmed. However, some cancer cells are resistant to this type of therapy and their resistance mechanisms remain poorly understood.
Researchers at the The Ottawa Hospital and University of Ottawa, under the leadership of Dr. Carolina Ilkow, have discovered that a common cellular mechanism, RNAi, allows cancer cells to fight back against cancer-fighting viruses. Their findings, recently published in the Journal for Immunotherapy of Cancer, show that blocking RNAi processes in tumours can make cancer cells more susceptible to OVs.
May 17, 2018
Combination of erectile dysfunction drugs and flu vaccine may help kill remaining cancer after surgery
A remarkable study led by Dr. Rebecca Auer from The Ottawa Hospital (TOH) shows that the unlikely combination of erectile dysfunction drugs and the flu vaccine may boost the immune system’s ability to clean up cancer cells left behind after surgery. This method demonstrated promising results in a mouse model, where it reduced the spread of cancer following surgery by 90 per cent. Now the approach will be tested in a first-of-its-kind clinical trial involving 24 patients at TOH.
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.
January 30, 2018
Early results from COMPASS trial demonstrate benefits of using genomic sequencing to guide treatment for pancreatic cancer
Genomic profiling has allowed physicians to customize treatments for patients with many types of cancer, but bringing this technology to bear against advanced pancreatic cancer has proven to be extremely difficult. OICR’s pancreatic cancer Translational Research Initiative, called PanCuRx, has been conducting a first-of-its-kind clinical trial called COMPASS to evaluate the feasibility of using real time genomic sequencing in pancreatic cancer care. The research team recently reported early results from the trial, which show how they overcame the challenges of genomic profiling specific to pancreatic cancer and gained new insights about the disease.
PanCuRx is focused on improving treatment for pancreatic adenocarcinoma (PDAC), the most common form of pancreatic cancer and the fourth leading cause of cancer death in Canada. The group’s approach centres around understanding the genetics and biology of PDAC to inform the selection of therapies, as well as the development of new treatments.
January 4, 2018
Researchers at The Ottawa Hospital and the University of Ottawa have found that a combination of two immunotherapies – oncolytic viruses and checkpoint inhibitors – was successful in treating triple-negative breast cancer in mouse models. Triple-negative breast cancer is the most aggressive and hard-to-treat form of the disease.
October 20, 2017
Researchers have discovered a new potential treatment for acute myeloid leukemia (AML). They found that boosting fat cells (adipocytes) within bone marrow with the use of a common diabetes drug slowed the growth of cancerous cells and promoted the regeneration of healthy blood cells.
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 12, 2017
Given the advancements in treating many other types of cancer, it may come as a surprise that outcomes for patients with the most deadly form of ovarian cancer have not improved in 50 years. This form, known as High Grade Serous Ovarian Cancer (HGSOC), accounts for 80 per cent of ovarian cancer deaths in Canada. Surgery and chemotherapy can be effective, but ultimately three-quarters of women with HGSOC will see their disease return. To deliver better outcomes for patients, OICR has launched a new ‘all star team’ of ovarian cancer researchers.
July 11, 2017
The body’s immune system is incredibly powerful. Its ability to detect and destroy various pathogens makes it central to maintaining good health. While we all know the role it plays in fighting the common cold or flu, many do not know that it has recently been enlisted by scientists in the fight against cancer. Researchers in a field known as immuno-oncology are working to find ways to turn on the body’s defences to locate and destroy tumour cells. OICR recently established a team of expert scientists and clinicians to develop and test new immunotherapies to help patients.