January 4, 2021
Researchers discover brain cancer may develop when tissue healing runs amok, uncovering new approaches to combat the deadly disease
The healing process that follows a brain injury, such as an infection or a stroke, could spur tumour growth when the new cells generated are derailed by mutations, Toronto scientists have found. This discovery could lead to new therapy for glioblastoma patients who currently have limited treatment options with an average lifespan of 15 months after diagnosis.
The findings, published today in Nature Cancer, were made by an interdisciplinary team of researchers from OICR, the University of Toronto’s Donnelly Centre for Cellular and Biomolecular Research, The Hospital for Sick Children (SickKids) and the Princess Margaret Cancer Centre who are also on the pan-Canadian Stand Up to Cancer (SU2C) Canada Dream Team that focuses on a common brain cancer known as glioblastoma.
“Our data suggest that the right mutational change in particular cells in the brain could be modified by injury to give rise to a tumour,” says Dr. Peter Dirks, senior author of the study, OICR-supported researcher, Dream Team co-leader, and Head of the Division of Neurosurgery and a Senior Scientist in the Developmental and Stem Cell Biology program at SickKids. “We’re excited about what this tells us about how cancer originates and grows and it opens up entirely new ideas about treatment by focusing on the injury and inflammation response.”
The research group, led in part by OICR and Princess Margaret’s Dr. Trevor Pugh, applied the latest single-cell RNA sequencing and machine learning technologies to map the molecular make-up of the glioblastoma stem cells (GSCs), which Dirks’ team previously showed are responsible for tumour initiation and recurrence after treatment.
Equipped with these single-cell analysis methods, the research group was able to accurately differentiate and study different types of tumour cells. Through analyzing 26 tumours and nearly 70,000 cells, they found new subpopulations of GSCs that bear the molecular hallmarks of inflammation.
This finding suggests that some glioblastomas may start to form when the normal tissue healing process is derailed by mutations, possibly even many years before patients become symptomatic, Dirks says. Once a mutant cell becomes engaged in wound healing, it cannot stop multiplying because the normal controls are broken and this spurs tumour growth, according to the study.
The study’s authors, including co-leading researcher, Dr. Gary Bader from the Donnelly Centre as well as graduate students including Owen Whitley and Laura Richards, are now working to develop tailored therapies target these different molecular subgroups.
“There’s a real opportunity here for precision medicine.” says Pugh, who is Director of Genomics at OICR and the Princess Margaret Cancer Centre. “To dissect patients’ tumours at the single cell level and design a drug cocktail that can take out more than one cancer stem cell subclone at the same time.”
In addition to funding from the Stand Up To Cancer Canada Cancer Stem Cell Dream Team: Targeting Brain Tumour Stem Cell Epigenetic and Molecular Networks, the research was also funded by Genome Canada, the Canadian Institutes for Health Research, the Ontario Institute for Cancer Research, Terry Fox Research Institute, the Canadian Cancer Society and SickKids Foundation.
November 18, 2020
Ontario cancer research leaders, Drs. Geoff Fong, Trevor Pugh and Lincoln Stein recognized as Highly Cited Researchers by Clarivate for their influential work
OICR is proud to celebrate the recognition of three Ontario cancer research leaders, Drs. Geoffrey Fong, Trevor Pugh and Lincoln Stein as Clarivate’s Highly Cited Researchers of 2020. This recognition demonstrates the incredible global impact of Ontario’s researchers and underscores the importance of sharing knowledge for greater progress around the world.
Fong, Pugh and Stein, who are senior OICR investigators and leaders, have led several international scientific collaborations that have uncovered valuable knowledge and informed disease control and management strategies in Canada and around the world.
- Dr. Geoffrey Fong leads the International Tobacco Control Policy Evaluation Project, which conducts cohort studies on the implementation of evidence-based tobacco control policies. The ITC Project has conducted studies in 29 countries, inhabited by more than 50 per cent of the world’s population.
- Dr. Trevor Pugh, who was recently named one of Canada’s Top 40 Under 40, leads highly-collaborative genomics studies that are focused on applying sequencing analysis in the clinic. His landmark cancer genome studies have advanced research across different cancer types and his work continues to make precision cancer medicine a reality.
- Dr. Lincoln Stein has led large international data sharing consortia, such as the International HapMap Consortium and the International Cancer Genome Consortium, which have led to highly-cited scientific tools and discoveries. The tools, data and knowledge resulting from these consortia have been used by tens of thousands of people around the world.
“We’re proud that cancer researchers here in Ontario are making a worldwide impact that will improve the prevention, diagnosis and treatment of cancer,” says Dr. Laszlo Radvanyi, President and Scientific Director of OICR. “I congratulate Drs. Fong, Pugh and Stein on this well-deserved recognition.”
The highly-anticipated annual list identifies researchers who demonstrated significant influence in their field or fields through the publication of multiple highly cited papers during the last decade. Their names are drawn from the publications that rank in the top one per cent by citations for field and publication year in the Web of Science citation index. Clarivate’s methodology draws on the data and analysis performed by bibliometric experts and data scientists at Clarivate’s Institute for Scientific Information.
The full 2020 Highly Cited Researchers list and executive summary can be found online here.
October 29, 2020
Dr. Trevor Pugh, OICR Senior Investigator, OICR Director of Genomics and Senior Scientist, Princess Margaret Cancer Centre has been named a Recipient of Canada’s Top 40 Under 40 for 2020.
The annual award was founded by Caldwell and recognizes 40 exceptional Canadian leaders who are visionaries, creative problem-solvers, inspire others, give back to the community and are under the age of 40.
Pugh and his fellow awardees were selected from over 900 nominees by an independent advisory board, comprising more than 25 business leaders from across Canada. Honourees were chosen on four key criteria: vision and innovation, leadership, impact and influence, and social responsibility.
When told that he had won, Dr. Pugh was elated.
“I could not believe it,” he said. “I’m tremendously excited. I really look forward to connecting with the Top 40 Under 40 community. It is very gratifying to see genome science and translational science – which has a direct impact on patient care – be recognized as an important field along with business luminaries.”
Pugh is a world-leading cancer genomics researcher and molecular geneticist whose mission is to use comprehensive genomic profiling and molecular technologies to guide the treatment of patients.
After receiving a PhD in medical genetics from the University of British Columbia, he did further postdoctoral work at Harvard Medical School, Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), as well as the Dana-Farber Cancer Institute.
He leads a multidisciplinary lab with 24 staff and trainees, and oversees 55 research staff at one of the largest genomics facilities in Canada at OICR and the Princess Margaret Cancer Centre. He is also an Associate Professor in the Department of Medical Biophysics at the University of Toronto.
Pugh is listed on the 2019 Highly Cited Researchers List by Clarivate Analytics. This list recognizes researchers whose published work has ranked in the top 1 per cent by citations of other researchers the world over.
He has also developed novel genomics technologies, including a new method which assesses and monitors if immune cells have been activated to fight cancer cells.
“I congratulate Trevor on being named to the prestigious Canada’s Top 40 Under 40. Through his cutting-edge research and leadership, Trevor is creating a future in which genomics are a routine part of cancer detection and precision treatment,” says Dr. Laszlo Radvanyi, President and Scientific Director, OICR. “Through his work at OICR I have seen firsthand Trevor’s outstanding commitment to his field, the collaborative and transparent spirit in his work, and his heartfelt desire to improve the lives of those with cancer.”
As a clinical molecular geneticist, genome scientist, and computational biologist, Pugh’s goal is to bring cutting-edge genomic technologies into routine use in cancer clinics – especially vital as the latest cancer treatments are increasingly based on genetic information.
Known widely for his leadership of numerous cancer genome research projects, Pugh’s expertise in clinical genomics has been foundational to the launch of the national Terry Fox Marathon of Hope Cancer Centres Network, which has become the nation-wide focal point to accelerate precision medicine for cancer. The Network will unite top-tier researchers and clinicians to test cutting-edge technologies in the clinic, share data and results for each cancer patient in Canada and provide access to any clinical trial – no matter where patients live.
This will give us a true and accurate representation of cancer as it occurs in populations across Canada, says Pugh, and will help us get answers to questions such as:
“How often does this genetic change occur in the population? What treatments did cancer patients get that worked best for specific or rare molecular cancer subtypes?
“We have no way of knowing or asking for that information now.”
Pugh’s research is also focused on detecting cancer as early as possible – even before it is diagnosed.
While screening tests exist for some cancers – such as mammography, colonoscopy and prostate specific antigen – most cancers do not have a non-invasive, early screening option.
“That is worrisome for people, especially those at high-risk for less frequent but lethal cancers,” says Pugh. “We want to change that using annual blood tests. The vision is early cancer screening for everybody, for every cancer type.”
With OICR’s support, Pugh and co-lead Dr. Raymond Kim of the Princess Margaret Cancer Centre are leading CHARM, a study that will test the blood samples of people without cancer to look for early traces of the disease. Data from this study will help scientists track how blood and immune systems change as people develop cancer, and how different environments and stressors affect the cancer risk.
“If we want to increase the speed at which patients can benefit from new treatments, we have to promote cross-training between everyone in healthcare: clinicians, scientists, computer whizzes, lab technologists, patients,” says Pugh. “We urge everyone to step outside their comfort zones, work together on a science project, learn a new skill and to collaborate!”
Adapted from an original post by the University Health Network.
August 28, 2020
OICR-supported researchers and collaborators discover indicators in the blood that may predict which patients will respond to the immunotherapy drug, pembrolizumab
Adapted from UHN’s Media Release.
Immunotherapy can shrink tumours and prolong survival for certain cancer patients, but clinicians don’t yet know which patients will benefit from these treatments. OICR-supported researchers and collaborators at the Princess Margaret Cancer Centre have made a discovery that could help identify those patients who may benefit and match them with potentially life-saving therapies.
In their study, recently published in Nature Cancer, the research group found that the changing levels of tumour fragments, or circulating tumour DNA (ctDNA), in a patient’s blood can be used to predict whether they will respond to the immunotherapy drug pembrolizumab.
The study lays the foundation for researchers to develop an easy, non-invasive and quick blood test to determine who will benefit from the drug and how well their disease is responding to treatment.
“While we have known for some time that cancer disease burden can be monitored by measuring tumour DNA in the blood, we are excited to report that the same concept can be applied to track the progress of patients being treated with pembrolizumab,” says co-first author Cindy Yang, PhD Candidate in Dr. Trevor Pugh’s lab at the Princess Margaret Cancer Centre and OICR. “This will hopefully provide a new tool to more accurately detect response and progression in patients undergoing immune checkpoint inhibitor therapy. By detecting progression early, patients may have the opportunity to undergo subsequent lines of treatment in a timely fashion.”
The benefits of blood tests
Conventionally, imaging scans – such as computerized tomography (CT) scans – and other methods are used to monitor a patient’s cancer. This study suggests a simple and quicker blood test as an alternative to these scans.
“Although important, computerized tomography (CT) and other scans alone will not tell us what we need to know quickly or accurately enough,” says senior author Dr. Lillian Siu, Senior Scientist and medical oncologist at the Princess Margaret Cancer Centre.
Dr. Scott Bratman, radiation oncologist and Senior Scientist at the Princess Margaret Cancer Centre and co-first author of the study, points out that it may take many months to detect whether a tumour is shrinking with various imaging scans.
“New next-generation sequencing technologies can detect and measure these tiny bits of cellular debris floating in the blood stream accurately and sensitively, allowing us to pinpoint quite quickly whether the cancer is active.”
This study represents one of the many emerging applications of using ctDNA to guide treatment decisions. It is one of the first to show that measuring ctDNA could be useful as a predictor of who responds well to immunotherapy across a broad spectrum of cancer types.
The prospective study analyzed the change in ctDNA from 74 patients, with different types of advanced cancers, being treated with pembrolizumab. Of the 74 patients, 33 had a decrease in ctDNA levels from their original baseline levels to week six to seven after treatment with the drug. These patients had better treatment responses and longer survival. Even more striking was that all 12 patients who had clearance of the ctDNA to undetectable levels during treatment were still alive at a median follow-up of 25 months.
Conversely, a rise in ctDNA levels was linked to a rapid disease progression in most patients, and poorer survival.
“Few studies have used a clinical biomarker across different types of cancers,” says Siu, who also co-leads OICR’s OCTANE trial. “The observation that ctDNA clearance during treatment and its link to long-term survival is novel and provocative, suggesting that this biological marker can have broad clinical impact.”
Innovation and translation
This study is part of a larger flagship clinical trial, INSPIRE, which has enrolled more than 100 patients with head and neck, breast, ovarian, melanoma and other advanced solid tumours. INSPIRE brings together researchers from many disciplines to investigate the specific genomic and immune biomarkers in patients that may predict how patients will respond to pembrolizumab.
INSPIRE is made possible by collaborations across institutes and industries with expertise from those applying genomics to research and those applying genomics in the clinic.
“INSPIRE is an incredibly collaborative initiative that is a blend of big genomics – looking at large trends across many individuals – and highly-personalized genomics – looking at mutations within each patient sample,” says Pugh, co-senior author, Senior Scientist at Princess Margaret and Senior Investigator and Director of Genomics at OICR. “This is a modern approach to the translation of clinical genomics.”
“As a PhD student, this project gave me the unique opportunity to work in a highly collaborative intersection with industry, clinical, and academic partners,” says Yang. “It is very exciting to see translational research in action.”
Read the UHN Media Release.
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.
May 31, 2019
In May, OICR welcomed Dr. Trevor Pugh as Director of Genomics and Senior Principal Investigator. Trevor is a cancer genomics researcher and board-certified molecular geneticist who has led the Princess Margaret Cancer Centre-OICR Translational Genomics Laboratory (PM-OICR TGL) since 2016.
In his new role, he will lead the OICR Genomics program, which brings together the Princess Margaret Genomics Centre, OICR’s Genome Technologies, Translational Genomics Laboratory and Genome Sequence Informatics teams under an integrated initiative to support basic, translational and clinical research. Here, Pugh describes some of his strategies and how he plans to take on this ambitious mandate.
You’re involved with a number of projects across many disease sites and you collaborate with researchers from vastly different areas of cancer research. Can you summarize what you focus on?
Simply put – I want to use genome technologies to guide the best patient care. The overall philosophy is to extract as much genomic information as we can from small amounts of tumour tissue, and turn that information into knowledge so that clinicians and patients can make targeted treatment decisions. I also want to open up these comprehensive data for researchers to mine and find new cures for these cancers.
Whether they are a graduate student working on myeloma or a postdoc working on liver cancer, we all learn from one another’s disease specialties.
And yes – I am involved with many areas of cancer research. Every member in my lab speaks the same genomics language. Whether they are a graduate student working on myeloma or a postdoc working on liver cancer, we all learn from one another’s disease specialties. We do genomics in a similar way as there are many genomic commonalities across cancer types and computational algorithms or infrastructure we build for one project invariably get reused for another project.
You are a board-certified molecular geneticist and a genomics researcher, but you also have a background in bioinformatics and software development. How do you balance making tools and making discoveries?
The tools we create and the research we perform go hand in hand. You can’t make discoveries without the infrastructure, and it is hard to develop technologies successfully without a guiding scientific question. With that said, the software that we make is designed to help not only our own research and clinical projects, but those of others. If we can make software work for us really well, we want to share it and make it easier for groups and labs across Ontario and around the world. This also holds for the data we generate, as there is great value to integrating our data with similar data sets from other hospitals.
How will this new role help you do that?
I have a few main goals in this role that I’m excited about. The first and the largest is to integrate the Princess Margaret Genomics Centre, PM-OICR TGL, Genome Technologies and Genome Sequence Informatics into one fully-coordinated machine. The people, tools and methods that we have at OICR and Princess Margaret are incredible and the infrastructure already in place can serve as a powerful vehicle for both research and clinical applications. In the first two weeks, I’ve been really impressed with how the leads of these programs have come together to form concrete plans for making this a reality.
The part that excites me about my new role is the O in OICR. Within this position, I can have a provincial outlook on translational research which is important as genomics research becomes increasingly dependent on multi-centre studies and inter-institutional collaborations. I think OICR can help facilitate a future where sharing ideas, data, and knowledge between institutions is much easier than it is today. I’m excited to help take things that work locally and make them available and easy-to-use across the entire province, so that we can benefit from the advances made by our neighbours. We are stronger when we work together in a collaborative way.
OICR is well-known as a developer of similar high-quality data sharing systems and I am looking forward to integrating these efforts to support our internal genomics enterprise
It sounds like a lot of your work addresses local needs, but how do you have so many international collaborations?
In computational biology, a lot of our concerns and challenges are shared with other groups as well. For example, the cBioPortal data sharing platform was originally built at Memorial-Sloan Kettering to allow researchers to easily query data from The Cancer Genome Atlas project. This initiative soon grew to include a team at Dana-Faber and now the software is fully open-source with five core, NIH-funded teams contributing to its development, including my own lab. In addition, there are groups working on improving and enhancing cBioPortal instances around the world as it expands to new applications beyond genomics. cBioPortal has emerged as a very powerful resource rooted in an international crowdsourcing model. Naturally, OICR is well-known as a developer of similar high-quality data sharing systems and I am looking forward to integrating these efforts to support our internal genomics enterprise, as well as national and international data sharing networks.
You’ve been involved with the evolution of genomics over the last two decades. What technologies excite you these days?
Hands down, it’s single cell sequencing. This is an amazing technology that allows us to see parts of the tumours that we could never see before. In one of my projects, we’re looking at each cancer population within a tumour sample and mapping each population to a drug treatment. With Drs. Benjamin Haibe-Kains, we’re applying this concept across hundreds of thousands of cells from brain tumours we have sequenced in collaboration with Peter Dirks and from myeloma cells with Suzanne Trudel. If we can find distinct clones – or types of cells – with tailored treatment options, we could potentially eradicate the cancer entirely using combination therapies. I think the future of precision medicine is dependent on single cell technology and I look forward to integrating this technology into clinical studies with collaborators at cancer centres across the province.
December 13, 2018
What can we gain from looking at the outliers?: An investigation into long and short-term ovarian cancer survivors
Researchers investigate the clinical, molecular and microenvironment factors that contribute to extreme therapy response and resistance in ovarian cancer patients
Some patients with high-grade serous ovarian cancer (HGSOC) respond exceptionally well to therapy, while others experience rapid disease relapse. The mechanisms behind these disparate outcomes are poorly understood, but a group of researchers based at the Princess Margaret Cancer Centre (PM) supported by OICR’s Ovarian Cancer Translational Research Initiative (TRI) are working to change that.Continue reading – What can we gain from looking at the outliers?: An investigation into long and short-term ovarian cancer survivors