January 20, 2020
OICR researchers identify novel causes of cancer progression in the non-coding genome, opening new lines of investigation for several cancer types
Toronto – (January 20, 2020) In an unprecedented pan-cancer analysis of whole genomes, researchers at the Ontario Institute for Cancer Research (OICR) have discovered new regions of non-coding DNA that, when altered, may lead to cancer growth and progression.
The study, recently published in Molecular Cell, reveals novel mechanisms of disease progression that could lead to new avenues of research and ultimately to better diagnostic tests and precision therapies.
Although previous studies have focused on the two per cent of the genome that codes for proteins, known as genes, this study analyzed mutation patterns within the vast non-coding regions of human DNA that control how and when genes are activated.
“Cancer-driver mutations are relatively rare in these large non-coding regions that often lie far from genes, presenting major challenges for systematic data analysis,” says Dr. Jüri Reimand, investigator at OICR and lead author of the study. “Powered by novel statistical tools and whole genome sequencing data from more than 1,800 patients, we found evidence of new molecular mechanisms that may cause cancer and give rise to more-aggressive tumours.”
The research group analyzed more than 100,000 sections of each patient’s genome, focusing on the often-overlooked non-coding regions that interact with genes through the three-dimensional genome. One of the 30 key regions discovered was predicted to have a significant role in regulating a known anti-tumour gene in cancer cells, despite being more than 250,000 base pairs away from the gene in the genome. The group performed CRISPR-Cas9 genome editing and functional experiments in human cell lines to explore the cancer-driving properties of this non-coding region.
“We characterized several non-coding regions potentially involved in oncogenesis, but we’ve just scratched the surface,” says Reimand. “With our algorithms and the rapidly growing datasets of patient cancer genomes and epigenetic profiles, we look forward to enabling future discoveries that could lead to new ways to predict how a patient’s cancer will progress and ultimately new ways to target a patient’s disease or diagnose it more precisely.”
Reimand’s research group developed the statistical methods behind this study and made them freely available for the research community to use. These methods have been rigorously tested against other algorithms from around the world.
“Looking into the non-coding genome is really important because these vast sections regulate our genes and can switch them on and off. Mutations in these regions can cause these regulatory switches to act abnormally and potentially cause – or advance – cancer,” says Helen Zhu, student at OICR and co-first author of the study. “We’ve shown that our method, called ActiveDriverWGS, can excavate these regions and pinpoint specific areas that are important to cancer growth.”
“Although these candidate driver mutations are rare, we now have the first experimental evidence that one of the mutated regions regulates cancer genes and pathways in human cell lines,” says Dr. Liis Uusküla-Reimand, Research Associate at The Hospital for Sick Children (SickKids) and co-first author of the study. “As the research community collects more data, we plan to look deeper into these regions to understand how the mutations alter gene regulation and chromatin architecture in specific cancer types to enable the development of new precision therapies to patients with these diseases.”
This study was supported by OICR through funding provided by the Government of Ontario, and by the Canadian Institutes of Health Research (CIHR), the Cancer Research Society (CRS), the Estonian Research Council, and the Natural Sciences and Engineering Research Council of Canada (NSERC).
Whole genome sequencing data used in this study was made available by the International Cancer Genome Consortium’s Pan-cancer Analysis of Whole Genomes Project (ICGC PCAWG), also known as the PCAWG Project or the Pan-Cancer Project.
January 13, 2020
Researchers identify five subtypes of pancreatic cancer, uncovering new opportunities for targeted treatment of the aggressive disease
Toronto – (January 13, 2020) Researchers at the Ontario Institute for Cancer Research (OICR) and the University Health Network (UHN) have discovered detailed new information about the subtypes of pancreatic cancer. A better understanding of the disease groups may lead to new treatment options and improved clinical outcomes for this lethal disease.
The study, published today in Nature Genetics, represents the most comprehensive analysis of the molecular subtypes of pancreatic cancer to date. Through detailed genomic and transcriptomic analyses, the research group identified five distinct subtypes of the disease (Basal-like-A, Basal-like-B, Classical-A, Classical-B, and Hybrid) with unique molecular properties that could be targeted with novel chemotherapies, biologics and immunotherapies.
“Therapy development for pancreatic cancer has been hindered by an incomplete knowledge of the molecular subtypes of this deadly disease,” says lead author Dr. Faiyaz Notta, Co-Leader of OICR’s Pancreatic Cancer Translational Research Initiative (PanCuRx) and Scientist at UHN’s Princess Margaret Cancer Centre. “By rigorously analyzing advanced pancreatic cancers – which is the stage of disease that most patients have when they’re diagnosed – we were able to create a framework. This will help us develop better predictive models of disease progression that can assist in personalizing treatment decisions and lead to new targeted therapies.”
The study is based on data from more than 300 patients with both early stage and advanced pancreatic cancer who participated in COMPASS, a first-of-its-kind clinical trial that is breaking new ground in discovery science and personalized pancreatic cancer treatment. COMPASS is enabled by advanced pathology laboratory techniques at UHN and OICR, and next generation sequencing at OICR.
“Most pancreatic cancer research is focused solely on early stage – or resectable – tumours, but in reality, pancreatic cancer is often found in patients after it has advanced and spread to other organs,” says Notta. “COMPASS allowed us to look into these advanced cancers while treating these patients, develop a better understanding of the biology behind metastatic pancreatic cancer, and shed light on the mechanisms driving disease progression.”
Interestingly, the Basal-like-A subtype, which had been difficult to observe before this study, was linked with a specific genetic abnormality. Most of the Basal-like-A tumours harboured several copies of a mutated KRAS gene, also known as a genetic amplification of mutant KRAS. The research group hypothesizes that some of the subtypes arise from specific genetic changes that occur as pancreatic cancer develops.
“This research opens new doors for therapeutic development,” says Dr. Steven Gallinger, Co-Leader of OICR’s PanCuRx, Surgical Oncologist at UHN and Senior Investigator, Lunenfeld Tanenbaum Research Institute at Mount Sinai Hospital. “We look forward to capitalizing on the promise of these discoveries, building on our understanding of pancreatic cancer subtypes, and bringing new treatments to patients with the disease.”
This research was supported by OICR through funding provided by the Government of Ontario, and by the Wallace McCain Centre for Pancreatic Cancer by the Princess Margaret Cancer Foundation, the Terry Fox Research Institute, the Canadian Cancer Society Research Institute, the Pancreatic Cancer Canada Foundation, the Canadian Friends of the Hebrew University and the Cancer Research Society (no. 23383).
January 10, 2020
OICR-led international research group develops new open-source software to determine the accuracy of computational methods that can map the genetic history of tumour cells.
A cancer patient’s tumour is often made up of many cells with different genetic traits that can evolve over time. Interest in tumour evolution has grown over the last decade, giving rise to several new computational tools and algorithms that can characterize genetic diversity within a tumour, and infer patterns in how tumours evolve. However, to date there has been no standard way to compare these tools and determine which are most accurate at deciphering these data.
The genetic differences between tumour cells can tell us a lot about a patient’s disease and how it evolves over time – Adriana Salcedo
In a study recently published in Nature Biotechnology, an OICR-led international research group released new open-source software that can be used to judge the accuracy of these novel algorithms.Continue reading – New open-source software judges accuracy of algorithms that predict tumour evolution
January 9, 2020
A message from Dr. Laszlo Radvanyi, OICR’s President and Scientific Director:
“On behalf of OICR I would like to express our sincere condolences to all those affected by the flight PS752 tragedy in Iran. Many of those who were lost were students and researchers at Canadian universities, making great contributions to cancer research and other fields by passionately applying their talents to tackle society’s greatest challenges. Our thoughts are with our university partners and their communities during this difficult time.”
December 19, 2019
Dr. Victoria Hoskin, OMPRN grantee, wins best poster presentation at the 2019 Terry Fox Research Institute Ontario Node Research Symposium for her novel approach to preventing cancer metastasis
The vast majority of cancer-related deaths are caused by cancers that have spread – or metastasized – to other organs. Breast cancer cells, for example, often spread to nearby lymph nodes where they can settle, grow and spread to more distant organ sites, evading surgery and chemotherapy treatment. Dr. Victoria Hoskin has set out to stop these migrating cancer cells in their tracks.
Earlier this year, Hoskin and an interdisciplinary team of researchers at Queen’s Cancer Research Institute (QCRI), found that a specific protein, ezrin, which plays a key function in cancer metastasis, may also have an important immune-modulating role. They went on to find that when ezrin is blocked, the immune system’s T-cells can better recognize, engage and kill the migrating cancer cells in surrounding lymph nodes. As she describes in her recent Oncotarget editorial, these findings may represent a new method to not only prevent cancer metastasis, but to also engage the immune system.
“When we blocked ezrin, we saw that the cancer cells couldn’t migrate and invade into other tissues,” says Hoskin, who is a Postdoctoral Fellow at QCRI. “We’re excited by these findings because they point to a new way to reduce the spread of cancer cells and to potentially boost the immune response against these cancer cells.”
Throughout the course of her research, which was supported in part by the Ontario Molecular Pathology Research Network (OMPRN), Hoskin helped develop a novel experimental animal model that allowed her and her team to track and monitor cancer and immune cells in vivo. The model, she describes, was the critical tool behind her discovery, allowing her to look deeper into the behavior of cancer cells and T-cells within specific organs.
Last week, Hoskin presented her research at the 2019 Terry Fox Research Institute Ontario Node Research Symposium. Among more than 120 other presenters, she won one of three poster presentation awards. Other presentation award recipients included:
- Parasvi Patel, PhD Candidate, University of Toronto and Princess Margaret Cancer Centre
- Noor Shakfa, MSc Candidate, Queen’s University and Queen’s Cancer Research Institute
Hoskin and her collaborators plan to further investigate how T-cells interact with cancer cells in the absence of ezrin.
“What we’ve found is not only scientifically interesting, it could be clinically significant,” says Hoskin. “Metastasis is a serious challenge and our research efforts are dedicated to finding a new solution.”
December 6, 2019
OICR-funded clinical trial shows value in advanced biopsy techniques for men with low-risk prostate cancer
Many of the 23,000 men across Canada who will be diagnosed with prostate cancer this year won’t need aggressive treatment. Instead, men with low-risk or slow-growing cancers may be offered ‘active surveillance’, where their healthcare team monitors their cancer closely with regular tests, scans and biopsies. Dr. Laurence Klotz, a world leader in active surveillance, is working to improve how surgeons in Ontario and across Canada perform these important prostate biopsies.
Klotz, who is a leading urologic surgeon and researcher at Sunnybrook Health Sciences Centre, teamed up with collaborators in London, Hamilton, Kitchener and Toronto to bring the latest MRI-guided prostate biopsy techniques to patients across the province. With OICR’s support, they evaluated the use of MRI-targeted biopsies, where a surgeon uses MRI images to help guide biopsy needles, relative to traditional biopsies, and found that the use of MRI results in 50 per cent fewer failures of surveillance. The findings from their two-year study were recently published in European Urology.
“As shown in other countries like the U.K. and Australia, using MRI before biopsies can reduce the diagnosis of insignificant cancers, selectively find aggressive cancers and reduce the number of false negatives,” says Klotz. “Our study showed that using MRI allows us to better pinpoint prostate cancers as they progress.”
Learnings from this study have helped inform the design of a new trial, called PRECISE, that is evaluating whether MRI can replace biopsies and spare some men from the associated side effects. Results from PRECISE will be submitted for publication in the next few months.
“We’ve laid the groundwork for better prostate cancer diagnosis,” says Klotz. “This means we’re one step closer to ensuring each man receives the most appropriate treatment for his individual cancer.”
December 5, 2019
Dr. Jane Bayani discusses how OICR is partnering with Thermo Fisher Scientific to bring new diagnostic tests from the lab into the clinic and how Genome Canada’s Genomic Applications Partnership Program (GAPP) is making that possible.
December 3, 2019
Funding will support Pugh’s innovative work in blood-based cancer detection and screening
Dr. Trevor Pugh, OICR’s Director of Genomics and Senior Investigator, has been named one of ten winners of the 2019 TD Ready Challenge.
The award, which is valued at $1 million, will support Pugh’s research over the next three years as he and collaborators, including Dr. Raymond Kim at the Princess Margaret Cancer Centre, develop an effective blood test for early cancer detection. The test will aim to help those with hereditary cancer syndrome, including individuals with Lynch Syndrome and people that carry BRCA1/2 mutations.
“People who carry genetic changes that place them at a high risk of cancer often face significant health, travel and financial burdens,” says Pugh. “Not all surveillance tests are readily accessible in remote or lower-income regions, so many of these people do not undergo necessary proactive preventative screening. We want to help fix that.”
With TD’s funding, Pugh, Kim, and collaborators across Canada will work to create an accessible blood-based screening test that can detect cancers earlier than current methods, and guide more personalized management of individuals at high risk of developing the disease.
“This project hinges on close collaboration and coordination with patients and clinical teams caring for them,” says Pugh. “TD’s support will further amplify the impact of our work, especially that of our team’s clinical lead, Dr. Kim, as he mobilizes hereditary genetics clinics for the benefit of patients across Canada.”
“TD’s support will allow our Ontario scientists to build on their leadership in early cancer detection and screening,” says Dr. Laszlo Radvanyi, President and Scientific Director of OICR. “We would like to thank TD for having the vision to support such an important project that will positively impact the health of Canadians. We would also like to congratulate Dr. Pugh and his team, and look forward to their continued progress in making cancer screening more accessible.”
As part of TD’s $1 billion commitment to community giving, the 2019 TD Ready Challenge encouraged organizations across North America to create innovative solutions that help increase equitable health outcomes and focus on preventative efforts. In total, TD awarded $10 million for the 2019 Challenge to deliver innovative healthcare solutions to those that need it most.
“OICR has brought forward a creative and scalable solution to help increase equitable health outcomes for underserved and remote communities,” says Andrea Barrack, Global Head, Sustainability and Corporate Citizenship, TD Bank Group. “Being a winner of the TD Ready Challenge is a testament to the skill, ingenuity, and vision of its creators, as well as their dedication to improving the health of their communities and opening doors to a more inclusive tomorrow.”
A full list of The 2019 Ready Challenge winners as well as more information about the challenge can be found at www.td.com/thereadychallenge.
November 26, 2019
Toronto – (November 26, 2019) Today, the Ontario Institute for Cancer Research (OICR) announced three new Investigator Award (IA) recipients, reinforcing OICR’s commitment to recruit and retain world-class cancer researchers across Ontario.
The awards are for up to $350,000 per year for up to six years, providing stable research funding and salary support for recipients to establish their laboratories and build their research platforms within Ontario. They bring with them expertise in big data, machine learning, multi-omics analysis and immuno-oncology. The new recipients are:
- Dr. Tricia Cottrell
Clinician Scientist I Award
Cottrell is a pathologist and immunologist from Johns Hopkins University who recently moved to Kingston to become an Assistant Professor at Queen’s University and Senior Investigator in the Canadian Cancer Trials Group. Cottrell focuses on mapping the interactions between the immune system and cancer cells as patients undergo treatment in order to develop new biomarkers that can better predict the course of a patient’s disease.
- Dr. Anna Panchenko
Senior Investigator Award
Panchenko was recently recruited to Kingston from the National Center for Biotechnology Information where she developed several methods and algorithms to study the molecular mechanisms behind cancer. Panchenko’s methods have been widely used by thousands of scientists from around the world to better understand the causes of cancer progression. She is now a Professor at Queen’s University and holds a Tier I Canada Research Chair.
- Dr. Parisa Shooshtari
Investigator I Award
Shooshtari is an Assistant Professor at Western University in London, where she is establishing her first laboratory as an independent researcher. Joining the OICR community with experience from Yale University, the Broad Institute of MIT and Harvard, and The Hospital for Sick Children (SickKids). Shooshtari brings unique expertise in developing computational, statistical and machine learning methods to understand the biology underlying complex diseases like cancer.
With their new appointments as OICR Investigators, Cottrell, Panchenko and Shooshtari join 25 other IA recipients as part of OICR’s collaborative cancer research community of more than 1,900 highly-qualified personnel across 23 Ontario institutes. Since its inception in 2006 the IA program has provided funding to recruit and keep world-class cancer researchers and clinician scientists in universities, hospitals and research centres across Ontario.
“Sustainable funding for talented scientists is critical to building a strong research ecosystem that will deliver the next wave of innovations and discoveries. The Investigator Award program is key to attracting and keeping top cancer researchers in Ontario,” says Dr. Christine Williams, Deputy Director and Interim Head, Clinical Translation at OICR. “We are particularly pleased that all three awards have been given to accomplished female scientists and are proud to offer our support as they establish their research programs in Ontario.”
“We are thrilled to welcome these highly-regarded researchers and look forward to their contributions to the health of Ontarians and the province’s cancer research sector,” says Hon. Ross Romano, Ontario’s Minister of Colleges and Universities. “Investing in top talent will allow Ontario to stay at the forefront of bio-medical research and realize the benefits of advancements in cancer prevention, diagnosis and treatment more quickly.”
As professors at their respective academic institutions, the three new IA recipients will take part in providing high-quality training to students in areas such as computer science and machine learning. Technological advancements and an evolving global economy are changing work in Ontario. These new, unique, cross-appointed positions will strengthen Ontario’s cancer research capacity while helping prepare students for careers in a rapidly-evolving knowledge-intensive industries.
For more information about the Investigator Award program, visit www.oicr.on.ca/investigator-awards.
November 21, 2019
International research group unlocks the promise of nanopore native RNA sequencing
Studying RNA may offer new answers to cancer – and the tools to read RNA directly are now in our hands.
An international research consortium, led in part by Dr. Jared Simpson at OICR, has developed new laboratory protocols and a suite of software tools that will allow the research community to exploit the promise of direct RNA sequencing.
These techniques, published recently in Nature Methods, represent the first large-scale exploration of human RNA using nanopore sequencers – the advanced handheld sequencing devices that can read long strands of RNA.
“Unlike traditional sequencing devices that read copies of RNA strands that are cut into little pieces, nanopore sequencing allows us to study long strands of RNA directly without losing important information in the copying and cutting process,” says Paul Tang, Computational Biologist at OICR and co-first author of the publication. “Our methods combine the power of reading RNA directly with the power of long-read sequencing, enabling an entirely novel way to study cancer biology.”
In collaboration with researchers at Johns Hopkins University and the University of California Santa Cruz, Tang and Simpson developed the software methods that could decode the output data from a nanopore sequencer. Their methods used a machine learning technique, called a Hidden Markov Model, to determine the letters of code within an RNA strand.
“With these methods, we’ve shown that you can leverage nanopore RNA sequencing to gain a lot of valuable information that we couldn’t have otherwise,” Tang says. “We’re very happy to see this work published because we are enabling others to study a new aspect of cancer biology and we look forward to the research discoveries to come.”
These new methods have been integrated into Simpson’s already-popular nanopolish software suite which is routinely used by the nanopore community around the world.
November 20, 2019
Research group draws on local health data to conduct the first ever population-level study of sarcoma treatment
The world knows Terry Fox but little is known about how his type of cancer is treated today.
Sarcoma – a relatively rare type of cancer that forms in tissues and bones – may be treated with a combination of surgery, chemotherapy and radiation, but treatment recommendations are vastly diverse. How well a treatment regimen will work is difficult to predict.
Recently, a Hamilton-based research group, supported in part by OICR, performed the first ever Canadian population-level study of sarcoma treatment. The study, which was recently published in Sarcoma, leveraged historical health data from nearly 4,700 patients and uncovered two key trends in treatment across various stages of the disease.
Firstly, they discovered an increasing use of radiation therapy for Stage 1 and Stage 2 sarcomas, also known as non-metastatic sarcomas. Dr. Anthony Bozzo, Orthopedic Surgery Resident at Hamilton Health Sciences and first author of the study says this trend aligns with our growing understanding of early stage sarcoma.
“This observation is concordant with two data-driven sarcoma prognostic models which generally display increased survival and lower chance for local recurrence for Stage 2 sarcomas treated with radiation therapy.”
Secondly, they found that over the ten-year period, the use of chemotherapy in patients with Stage 4 soft tissue sarcoma has significantly increased by 36 per cent.
“The trend in increasing chemotherapy use is surprising to us because the current literature does not indicate a significant survival benefit from chemotherapy in advanced soft tissue sarcomas,” says Dr. Bozzo. “Chemotherapy, however may benefit some patients and it may also be used for palliative purposes in others.”
The study group is now digging deeper into similar datasets to see if they can predict how a sarcoma patient would respond to treatment based on historical data. With this knowledge, they could provide the cancer care community with survival statistics that can help oncologists and patients create better treatment plans with more confidence.
Dr. Michelle Ghert, Orthopedic Oncology Surgeon with Hamilton Health Sciences, Professor at McMaster University and senior author of the study, comments on the importance of leveraging our local health data.
“We are fortunate in Ontario to have access to a centralized source of health data,” she says. “We can use this real-world evidence to see how research is applied in our health care system, find inconsistencies or gaps in our knowledge, and in turn, make recommendations to help improve cancer care locally and across Ontario.”
November 18, 2019
McMaster University researchers validate a new treatment approach that could help bring the benefits of Adoptive T-cell therapies to patients with solid tumours
Adoptive T-cell therapy (ACT) is an emerging form of immunotherapy that uses a patient’s own re-engineered immune cells to eliminate their cancer. Although ACT is effective against specific types of cancer, like certain blood cancers, these therapies are ineffective against the majority of common tumours.
Researchers at McMaster University are developing a new combination approach that could overcome the limitations of current ACT, and bring the benefits of this promising therapy to many more patients.
The approach, as recently described in The Journal of Clinical Investigation, combines ACT with specially-designed vaccines, called oncolytic virus vaccines (OVVs), to bring about the complete destruction of a solid tumour.
Dr. Scott Walsh, Postdoctoral Fellow in Dr. Yonghong Wan’s lab at McMaster University and first author of the publication, describes the “push and pull” mechanism behind their combination approach.
“We found that oncolytic viruses could stimulate the implanted T-cells to proliferate. In other words, they could push the cancer-fighting cells to multiply,” says Walsh. “Then we found that these viruses could also pull the cancer-fighting T-cells into the core of the tumour, which simply could not be done with ACT alone.”
In this study, the research group discovered that their ACT/OVV combination approach could engage the entire immune system to eliminate solid tumours and generate a long-term tumour-resisting effect in experimental animal models. Whereas current ACT can only kill specific tumour cells, their approach was effective at eliminating the various types of cells within solid tumours.
“Usually, ACT can only target the tumour cells that have a specific set of molecular markers. This is a problem because tumours can often shed these marked cells and return with a vengeance,” Walsh says. “Our approach engages the immune system as a whole, not just the re-engineered cells, to eliminate a broader variety of tumour cells and prevent the tumour from coming back over the long term.”
To bring this new approach into the next stage of development, the study group teamed up with experts across the province through OICR’s Immuno-oncology Translational Research Initiative. The team includes researchers with deep immuno-oncology expertise and extensive commercialization experience.
“Bringing this idea into the next stage of development requires collaboration across areas of expertise,” says Walsh, who holds a patent on the combination approach. “We’re looking forward to building on our past successes and using our collective expertise to move into more advanced animal models, and then onto clinical trials.”