February 19, 2021

OICR-supported collaboration discovers new method to stunt the growth of brain cancers

Inhibiting a key enzyme could help stop the growth of glioblastoma

Fewer than 10 per cent of people diagnosed with glioblastoma will survive beyond five years. Despite advances in understanding this deadly brain cancer, therapy options for this disease are severely limited. In a study recently published in Nature Communications, researchers have discovered that inhibiting a key enzyme, PRMT5, can suppress the growth of glioblastoma cells. Their findings demonstrate a novel approach to treating the disease, paving the way for a new class of therapeutics.

Dr. Peter Dirks, co-leader of OICR’s Brain Cancer Translational Research Initiative.

A multidisciplinary team with expertise in cancer stem cells, protein structures, small molecule development and multi-omic analyses enabled this discovery. The group, was co-led by Dr. Peter Dirks, Senior Scientist and Neurosurgeon at the Hospital for Sick Children (SickKids) and co-leader of OICR’s Brain Cancer Translational Research Initiative along with researchers at the Princess Margaret Cancer Centre, the Structural Genomics Consortium (SGC) and the University of Toronto. Many of the researchers involved in the study are also part of the Stand Up To Cancer (SU2C) Canada Cancer Stem Cell Dream Team, which receives support from OICR.

Through the study, they showed that inhibiting PRMT5 affected a large network of proteins that are important in cell division and growth, triggering cell senescence, and stopping the unrelenting division of cancer cells.

While PRMT5 inhibition has been previously suggested as a way to target brain and other cancers, no one has tested this strategy in a large cohort of patient tumour-derived cells that have stem cell characteristics, cells that are at the roots of glioblastoma growth.

They found that specific molecules – precursors to actual therapeutic drugs – inhibited the same enzyme, PRMT5, stopping the growth of a large portion of these patient-derived cancer stem cells. Many current drugs do not eliminate cancer stem cells, which may be why many cancers regrow after treatment.

“We used a different strategy to stop cancer cells from proliferating and seeding new tumours,” says co-senior author, Dr. Cheryl Arrowsmith, Senior Scientist at the Princess Margaret Cancer Centre who leads the University of Toronto site of the SGC. “By inhibiting one protein, PRMT5, we were able to affect a cascade of proteins involved in cell division and growth. The traditional way of stopping cell division has been to block one protein. This gives us a new premise for future development of novel, more precise therapies.”

“This strategy also has the opportunity to overcome the genetic variability seen in these tumours,” says co-senior author, Dirks, who also leads the SU2C Canada Dream Team. “By targeting processes involved in every patient tumour, which are also essential for the tumour stem cell survival, we side-step the challenges of individual patient tumour variability to finding potentially more broadly applicable therapies.”

The researchers also examined the molecular features of the patient-derived glioblastoma cells by comparing those that responded well to those that did not respond as well. They found a different molecular signature for the tumour cells that responded. In the future, this could lead to specific tumour biomarkers, which could help in identifying those patients who will respond best to this new class of drugs.

The research group will continue testing PRMT5 inhibitors to develop new therapies for people with glioblastoma.

“Right now, we have too few medicines to choose from to make precision medicine a reality for many patients,” says Arrowsmith. “We need basic research to better understand the mechanism of action of drugs, particularly in the context of patient samples. This is what will help us develop the right drugs to give to the right patients to treat their specific tumours.”

The research group also included OICR-affiliated scientists and staff researchers, Drs. Trevor Pugh, Mathieu Lupien, Benjamin Haibe-Kains, and Ahmed Aman.

Adapted from a SickKids news release.

February 17, 2021

OICR’s Dr. John Bartlett named one of the top-cited authors in the Journal of Clinical Oncology

Dr. John Bartlett

The Journal of Clinical Oncology (JCO), one of the most prestigious journals in cancer research, recently added Dr. John Bartlett to its list of most-cited authors following an analysis by the analytics firm Clarivate. A clinical practice guideline update by Bartlett and his coauthors was the third most-cited article JCO published in 2018. The guideline, on HER2 testing in breast cancer, has been cited an outstanding 276 times. Bartlett is Director of OICR’s Diagnostic Development Program, which is working to develop new tools to guide precision medicine for cancer.

February 3, 2021

Standards redefined: What lab accreditation means to OICR Genomics

OICR Genomics believes high-quality cancer research starts with high-quality data. Since inception, their labs have been committed to quality, and now accreditation is within reach

Standards are all around us – making our lives safer and easier in many ways. In both research and medicine, laboratory standards help evaluate a lab’s quality, reliability and efficiency. Research lab standards help scientists generate reliable data leading to reproducible discoveries, but in medicine, lab standards help clinicians make more accurate diagnoses and treatment decisions. These different applications call for different standards and sometimes different schools of thought.

Since inception, OICR Genomics has been building a bridge between research and medicine, developing new standards for innovative genomics technologies while refining lab procedures so they can serve as the trusted genomics services provider for Ontario’s cancer community. Today, OICR Genomics is proud to provide high-quality services for cancer researchers, clinicians, and the patients they serve.

The journey to accreditation

Achieving and maintaining accreditation is an exceptionally rigorous process that requires steadfast diligence and meticulous lab management over a sustained period of time. Since 2018, OICR Genomics has been developing and improving processes and procedures to achieve accreditation by the Institute for Quality Management in Healthcare (IQMH) and the College of American Pathologists (CAP), two well-recognized leaders in lab accreditation.

There are three key elements that make accreditation possible:

Dedicated people. Every member of OICR Genomics is important to the accreditation process. Accreditation requirements include effective documentation and training protocols, a strong track record of good lab practices, continuous sharing and monitoring of technical results, appropriate validation and uncertainty correction methods, an extensive array of standard operating procedures, and more. Successful accreditation requires the collective effort of all lab staff – from students to senior researchers.

“I’m proud of our team’s commitment to the community,” says Dr. Carolyn Ptak, Program Manager and Quality Assurance Lead of OICR Genomics. “We have a great group that is flexible, innovative and committed to quality.

Balanced priorities. Given the complex and rapidly evolving field of cancer genomics, many laboratories face challenges associated with compliance. New tools and innovations call for new standards. OICR Genomics continuously strives to balance innovation, performance, efficiency and safety under the leadership of Dr. Trevor Pugh.

“As research continues to evolve, OICR Genomics will continue to as well,” says Dr. Trevor Pugh, Senior Investigator and Director of the Joint Genomics Program at OICR and the Princess Margaret Cancer Centre. “We’re excited by the current advancements in genomics and we look forward to continuous improvement in the years to come.”

Stable support. Over the last fifteen years, OICR has mobilized the community to transform cancer care through collaborative networks, transformative initiatives and more. Many collaborators have recognized the value of working with OICR Genomics and it is with their consistent support that the foundations leading to accreditation were laid.

“We are thankful for all the talented scientists who have worked with us throughout the years on innumerable genomic sequencing projects,” says Dr. Paul Krzyzanowski, Director of the Genome Research Platform,  “Our  newly accredited services will be available to clinical, academic, and industrial research clients and we’re excited to be able to support a whole new scale and scope of projects.

For the community

Genomics has become a central discipline of cancer research. It has unlocked new opportunities to predict cancer earlier and match patients with the most effective medicines for their disease. In parallel, advances in research methods and sequencing technologies have expanded the affordability and accessibility of genetic sequencing. Reading human DNA and RNA is no longer a multi-year, multi-million-dollar initiative, it can be done in hours or days at a fraction of that cost. These opportunities, however, can only be realized through the translation of research and innovation. For OICR Genomics, translation is at the centre of their mission – and rigorous lab standards help accelerate translation.

Within the cancer community, OICR Genomics’ lab standards can mean different things to different people:

  • For the researcher, high lab standards and accredited lab services help you generate high-quality, reliable data in an efficient way. This means you can have more trust in your results and more reproducible discoveries.
  • For the patient, high lab standards can help ensure that the community is effectively gaining knowledge from your donated biological samples. Accreditation of your local genomics research lab can also help your care teams apply the most recent discoveries to your treatment planning.
  • For the province, these internationally recognized standards will help research teams use resources efficiently and effectively, maximizing the impact of finite resources, while attracting high-profile genomic studies to Ontario.

“Accreditation allows us to explore transformative new approaches to achieve health benefits,” says Dr. Laszlo Radvanyi, President and Scientific Director of OICR. “Ultimately, accredited lab protocols help our lab infrastructure serve as bridge between research and improved health.”

For more information on OICR Genomics’ services please visit the genomics services page or contact OICR Genomics.

February 3, 2021

Imagining the next 20 years and planning for the next five

How OICR is using strategic foresight to prepare for the future and inform its 2021-2026 Strategic Plan

OICR focuses on translating cancer research discoveries and transforming cancer care. Achieving this mission, however, is dependent on a myriad of factors beyond scientific research and development. Social, political, technological, economic and environmental factors all may play a role in driving the future of cancer research and care in Ontario and beyond.

As part of the process to develop its 2021-2026 Strategic Plan, OICR partnered with Dr. Peter Bishop, Professor Emeritus at the University of Houston, professional futurist and President of Strategic Foresight and Development, to investigate the possible futures of cancer research and care in Ontario and around the world. OICR plans to launch the 2021-2026 Strategic Plan in April 2021.

Read the full report in Foresight.

With the help of leaders from research institutes, hospitals and the public sector across Ontario, 20 key drivers were identified that may significantly affect the future of cancer, including an aging population, innovations in quantum computing and the growing focus on holistic health. The group then designed and evaluated potential future scenarios and derived four main insights that were used to inform OICR’s 2021-2026 Strategic Plan:

Data dilemmas
While health-related datasets continue to grow and new sources of data emerge, standards around data gathering, monitoring, integration, sharing and implementation remain unclear. These parameters affect how the cancer community implements precision medicine for people living with cancer. Through its 2021-2026 Strategic Plan, OICR’s computational biology and informatics research programs will continue to develop essential data tools and apply responsible data sharing standards, while strengthening Ontario’s global leadership in health data integration and federation through initiatives such as the Global Alliance for Genomics and Health, the International Cancer Genomics Consortium Accelerating Research in Genomic Oncology, Canada’s Digital Health and Discovery Platform, and the Ontario Data Integration Network.

Powerful patients
Integrating the perspectives of patients into research is becoming increasingly important to ensure that research ultimately leads to patient benefit. Over the next few decades, patients will increasingly have access to more information and misinformation, challenging the research and health communities to ensure patients receive the information they need to make informed decisions. To address these challenges, OICR will foster and grow meaningful partnerships with patients and caregivers to integrate patient values into OICR priorities. OICR is currently developing a Patient Family Advisory Council, which will advise on OICR’s patient partnership initiatives.

Funding fragility
As the cost and urgency of cancer drug development continue to increase, alternative funding for research and translation may become necessary. This challenge has become more apparent as the world looks to recover from the socio-economic impacts of the coronavirus pandemic. OICR will continue to strengthen partnerships within the cancer ecosystem over the next five years, to attract further investment in cancer research and innovation to Ontario. OICR will also build health services research expertise into critical research programs to evaluate the costs and benefits of emerging interventions to support the path between discovery and patient care.

Teetering trust
Trust between stakeholders in the cancer system – including patients, families, researchers and clinicians – is critical to progress in cancer research. Trust is imperative to data gathering, sharing and processing, and these data are necessary to make cancer detection and treatment more precise. Through the 2021-2026 Strategic Plan, OICR aims to work together with partners to ensure we remain and become an even more trusted custodian of patient data and scientific information to support high quality translational research, bridging the lab to the clinic.

“Our mission is based on translating cancer research discoveries to transform cancer care,” says Dr. Rebecca Tamarchak, Senior Director of Strategic Planning and Governance. “Integrating foresight into our strategic planning process is our way to proactively anticipate the future in order to develop a nimbler strategy.”

The strategic foresight workshop, which was hosted in late 2018, kicked off OICR’s multi-phase strategic planning process. The process, led by Tamarchak and OICR’s President and Scientific Director, Dr. Laszlo Radvanyi, has incorporated insights from extensive consultations with OICR staff, collaborators and the community.

“This strategic foresight study has reinforced the importance of enduring partnerships across the cancer research community and we look forward to strengthening those relationships over the next five years to maximize our impact on cancer patients and the Ontario economy,” says Tamarchak. “We’re excited to bring the 2021-2026 Strategic Plan into action.”

February 3, 2021

What we learned at the recent OICR-JLABS cell therapy symposium

OICR and Johnson & Johnson Innovation – JLABS @ Toronto launch the OICR-JLABS Cancer Symposium Series, featuring leaders, innovators and trail blazers in cell therapy

On January 28, OICR and JLABS @ Toronto hosted the inaugural symposium of their Cancer Symposium Series, focused on horizons and controversies in cell therapy for cancer treatment. Invited speakers from around the world took a deep dive into the promise of gene therapy and the key challenges that they’re working to overcome.

The event was hosted by the Regional Head of JLABS Canada, Allan Miranda, and OICR’s President and Scientific Director, Dr. Laszlo Radvanyi. Guest speakers included Dr. James Yang from the National Cancer Institute, Dr. Emily Titus, Vice President at Notch Therapeutics, and Dr. Michael Maguire, CEO of Avectas.

Event recap

  • Dr. Yang reviewed the notable advancements made in Adoptive T cell Therapy (ACT) for certain cancers, like melanomas. Despite these advancements, he emphasized the importance of further research since most of the common cancers that kill people have yet to be addressed using immunotherapy. His presentation outlined some key scientific and biological challenges in developing effective ACT for epithelial cancers, highlighting that epithelial cancers, which represent the vast majority of cancer cases, have a lower mutational burden relative to melanomas, often have a limited number of tumour-infiltrating lymphocytes, and are difficult to mimic in experimental models.
  • Dr. Titus presented Notch Therapeutics’ platform for generating T cells and other immune cells from stem cell lines. The team at Notch, which has expanded from Toronto to Vancouver and Seattle, is leveraging their platform to build a pipeline of sophisticated T cell therapeutic products.
  • Dr. Maguire shared Avectas’ automated GMP engineering platform, SOLUPORE, which is built to enable the ex-vivo manufacture of gene modified cell therapy products. He emphasized the importance for improved complex engineering solutions to address solid tumours.

The event highlighted the potential of cancer cell therapy and the technologies that will advance the field of cell therapy in the future. The event recording can be accessed here.

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January 27, 2021

OICR-led research well represented in Nature Communications’ editor’s selections

The high-impact, open-source journal Nature Communications has published an editor’s selection of interesting, recently published studies that “significantly move forward the rapid evolving field of cancer research”. OICR is prominently featured with eight of the 41 studies selected having an OICR senior researcher as an author. Many of the highlighted findings stem from the Pan-Cancer Analysis of Whole Genomes project, an unprecedented global collaboration led in part by OICR that generated the most comprehensive map of cancer genomes charted to date.

January 8, 2021

Q&A with new OICR Investigator Dr. Shraddha Pai on uncovering the hidden differences between cancers

OICR is proud to welcome Dr. Shraddha Pai to its Computational Biology Program as a Principal Investigator. Here, Pai discusses current challenges in understanding diseases and what motivates her to tackle some of the biggest challenges in biomedical research.

What are some of the research questions you’re interested in?

I’m very driven to understand why different people with the same cancer type, have different outcomes and respond differently to the same treatment. As genomic assays get cheaper, we learn more about molecular interplay in different cells, and our population datasets become larger and mature, we are able to integrate different layers of the genome and cell types, to try to get at this question. For example, we now believe there are four main types of medulloblastoma with different underlying molecular networks and outcomes. This field of research is called ‘precision medicine’: using patient profiles to match them with the most effective treatment. But really this is just a new phrase to describe what doctors have been doing since the dawn of medicine; it just means that now we’re using powerful computers and algorithms to find patterns in much larger and complex genomic datasets. The principle is the same.

As a trainee in Dr. Gary Bader’s group, I led the development of an algorithm that integrates several types of patient data to classify patients by outcome.  Our method – called netDx – adapts the idea of recommender systems, used by Netflix and Amazon, to precision medicine. Just as one would ask Netflix to “find movies like this one”, netDx helps identify patients “with a treatment profile like this”. In a benchmark, netDx out-performed most other methods in predicting binary survival in four different types of cancer. Importantly, netDx is interpretable, and recognizes biological concepts like pathways. This makes it a useful tool to get mechanistic insight into why a predictor is doing well, and provides a way to understand the underlying biology and perhaps drive rational drug design.

I also have a special interest in understanding the link between epigenetics and disease, particularly as this pertains to the brain. Epigenetics refer to molecular changes that change how the genome behaves – for example, turning a gene on or off in a given cell type. My own previous research in mental illness has found epigenetic biomarkers related to psychosis, which explain the distinctive features of this condition. The same may be the case in certain types of cancers, particularly those of developmental origin.

How do you plan to unravel these complex layers of biology?

My research program has two main goals. The first is to build models for precision medicine – predicting disease risk, treatment response – starting with population-scale datasets that have several types of patient data. I’m hoping to use existing and emerging data such as UK BioBank, CanPath, ICGC-ARGO and the Terry Fox Research Institutes’ datasets, and ongoing clinical trials, to identify which clinical outcomes are easily amenable to our approaches. The models my group builds will incorporate prior knowledge about genome organization and regulation, so that these are interpretable. For example, we will use epigenomic maps of specific tissue types, or data from single-cell resolution maps, pathway information, to find and organize relevant needles in the genomic haystack. This feature will give us interpretability, which is key to increasing confidence in a model, as well as to improving the understanding of cellular pathways that affect disease and eventual drug development.

My second goal is to understand the epigenomic contributions – particularly developmental changes – to cancer risk, using a combination of molecular biological, genomic and analytic techniques.

As I work toward these goals, I hope to collaborate on complementary projects, such as identifying DNA methylation changes in circulating tumour DNA and improving how we subtype adult tumours. These projects will hopefully lead to new biomarkers, and ultimately improvements to how we diagnose and treat cancer.

Importantly, the software that my team builds will also be openly available to the research community, so others can apply my methods to different types of diseases. I’m excited to get started.

Your work applies beyond cancer. How do you traverse these different disease areas?

The reclassification of disease based on molecular or other biomarkers, and how disease subtype affects risk and treatment response, isn’t unique to cancer – the same research questions extend to other types of disease such as metabolic diseases, autoimmune diseases and mental illness. At the end of the day, we are looking at the same system organized at the molecular, cellular and organ-level, with similar principles of genomic regulation and perhaps similar considerations for drug discovery. Our algorithms are based on these general principles and can therefore be used to answer similar questions for different disease applications, or very different types of cancer. Of course, it’s important to collaborate with teams that have domain expertise to make sure the algorithms are “fine-tuned” for a particular application, and I look forward to benefitting from those partnerships.

What excites you about this type of work?

I’m excited to join a community where basic research is so strongly connected to clinical purpose. Personally, I am very motivated by the prospect of a positive impact on patients within my lifetime and feel that my group’s work is more likely to have a valuable impact in an environment that combines basic and translational research. That said, we’re only just beginning to see the benefits of precision medicine and many challenges remain to bring genomic knowledge into practice. I hope that I can create more useful methods and models for precision medicine and improved clinical decision-making in the coming decade.

I’m especially excited to be at OICR because of the Institute’s access to clinical trials, strong genomics and computational biology program, and pharmacology team. If my group can find promising biomarkers and leads, we can work with OICR collaborators in the Genomics and Drug Discovery groups to move from basic research to application.

Read more about Dr. Shraddha Pai.

January 4, 2021

Brain cancer linked to tissue healing, study finds

A brain scan showing a top down view of a cross-section with a glioblastoma tumour highlighted in red. (Hellerhoff, Wikimedia Commons)

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.

December 17, 2020

nanoNOMe: New dual-purpose tool added to the Swiss Army knife of DNA sequencing

Dr. Jared Simpson and collaborators develop new nanopore-based methods to investigate two understudied aspects of disease biology

Studying DNA modifications may offer new insights into cancer – and the tools to read these changes are now in our hands.

In a recent publication in Nature Methods, OICR Investigator Dr. Jared Simpson and collaborators at Johns Hopkins University describe a new method to investigate two key aspects of disease biology, methylation and chromatin accessibility, simultaneously. These aspects can help describe how genes are organized and switched on and off in a cell, which may enable future progress in cancer research and discovery.

The group’s new method, coined nanoNOMe-seq, is built for nanopore sequencing – a fast, portable way to read long molecules of DNA. nanoNOMe serves as an additional tool that extends the utility of nanopore sequencing technologies.

“Our collaborators developed the lab protocols and we developed the analysis software to determine where DNA modifications occurred,” says Simpson. “Now, with this method, other researchers can investigate how DNA is modified within a cell to give an extra layer of information that the community can decode into new insights and discoveries.”

Dr. Michael Molnar, Scientific Associate in the Simpson Lab at OICR, led the development of the analysis software behind nanoNOMe.

“At times, it seemed like it might not be possible to develop a statistical model that could make sense of all the data,” says Molnar. “But we were able to persist and develop the nanoNOMe software, which showed a high degree of accuracy. We hope this method will enable others to discover long-range patterns and make new connections in sequencing data.”

nanoNOMe was first released as a preprint, which has already been cited in other scholarly articles including a tool for methylation pattern visualization, an analysis of human chromosome 8, and a published review on long-read sequencing among other publications. Simpson and Molnar’s collaborators plan to further investigate methylation and chromatin accessibility in human cancer cells with nanoNOMe.

“If you’re interested in understanding how methylation relates to open chromatin, then you can use this protocol,” says Simpson. “This is opening a new space for the community to explore interactions between chromatin and DNA methylation.”

December 9, 2020

Innovative tool pinpoints rare mutations that indicate the earliest phases of leukemia development

Dr. Sagi Abelson
Dr. Sagi Abelson, OICR Investigator, Assistant Professor at the University of Toronto and first author of the publication.

The tool can accurately distinguish real mutations from sequencing mistakes to improve the early detection of cancer

DNA mutations in cancer cells are caused by different processes, each of which leaves a genetic fingerprint that can provide clues to how the cancer develops. Researchers have now applied this understanding to reduce errors when reading DNA, allowing them to accurately and efficiently detect the smallest traces of mutated cells in the blood.

In a recent publication in Science Advances, an OICR-supported research group outlines a new and improved statistical model to reduce error rates in DNA sequencing data. They demonstrate that their model, called Espresso, outperforms current error suppression methods.

“When we isolate, amplify and try to read the individual building blocks of DNA, we encounter a lot of errors,” says Dr. Sagi Abelson, OICR Investigator, Assistant Professor at the University of Toronto and first author of the publication. “This is a major obstacle. The high error background makes it difficult to pinpoint authentic rare mutations. This is what Espresso aims to solve.”

To build an effective error-suppressing statistical model, the group assessed the different types of errors in their relative genomic contexts across more than 1,000 sequencing samples. Their approach was based on assessing the genetic fingerprints within these samples and mapping them to the regions around the errors to understand if the error was a true mistake, or if it was an important mutation.

“The key advantage of our method is that it allows scientists to read DNA more accurately without the need to duplicate efforts using a set of independent control measurements to estimate error rates,” says Abelson. “This means that researchers can be more efficient with their time and resources. They can do more with less. We’re proud to have developed methods that can make research more practical and simple, but also more effective, efficient and accurate.”

This model is built on Abelson’s prior research published in Nature, which discovered early indicators of acute myeloid leukemia (AML) in the blood up to 10 years before symptoms surfaced. With Espresso, the research group was able to develop and test a new strategy to predict leukemia development, which could predict up to 30 per cent of AML cases years before clinical diagnosis with extremely high specificity. Importantly, this study demonstrated that the risk of developing AML can be measured by looking into only a small number of genomic bases, which suggests a more practical route to clinical testing and implementation.

“This work builds on our prior research, which has shown that we can detect AML earlier than thought possible,” says Dr. John Dick, Senior Scientist at the Princess Margaret Cancer Centre, Co-lead of OICR’s Acute Leukemia Translational Research Initiative and co-senior author of the study. “With these methods, we’ve now shown that we can focus in on specific areas of DNA to detect those early traces of AML with higher accuracy than ever before.”

“These methods are essential to advancing personalized cancer care in practice,” says Dr. Scott Bratman, Senior Scientist at the University Health Network’s Princess Margaret Cancer Centre and co-senior author of the study. “With these tools, we can enable clinicians to treat cancer more effectively, tailor treatment decisions and monitor minimal residual disease. We look forward to furthering our research for patients today and those who will develop cancer in the future.”

December 2, 2020

Study uncovers new approach to mobilize the immune system against hard-to-treat breast cancers

Dr. Sam Workenhe. (University of Guelph)

Researchers at the University of Guelph and McMaster University create combination immunotherapy approach to treat breast tumours and other cancers

Over the last few decades, scientists have made significant progress in harnessing the immune system to treat cancers. Despite these advances, many types of cancer can still evade the immune system and current immunotherapies. Dr. Sam Workenhe is developing better treatment options for patients with these hard-to-treat diseases.

In his recent study, published in Nature Communications Biology, Workenhe and collaborators at the University of Guelph and McMaster University discovered a new combination immunotherapy approach for breast tumours and other cancers. Their approach leverages cancer-killing viruses, called oncolytic viruses, and chemotherapy to trigger tumour inflammation, stimulating the body’s immune system to control tumour growth. Their combination leveraged the oncolytic virus, oHSV-1, and the chemotherapy agent, Mitomycin-C.

The research team demonstrated the effectiveness of this treatment approach in mouse models of breast cancer. They found that that mice treated with this combination therapy lived approximately two months longer than untreated ones – a significant difference relative to the short lifespan of these mouse models.

“Simply put, we wake up the immune system,” says Workenhe, Assistant Professor at the University of Guelph’s Ontario Veterinary College and an OICR Joseph and Wolf Lebovic Fellowship Program awardee. “Our study proves that aggressive tumours without immune cells can be made to render an immune response. Understanding how to design treatments that can potentially activate the immune system against cancer can revolutionize the current standards of care.”

Additionally, the study delineated the anticancer mechanisms of their approach, detailing how each element kickstarts an immune response against the tumours. Workenhe, who is a trained veterinarian and a virologist, is now applying these findings to further study immune responses and inflammatory cell death in tumours.

“A lot of people are excited about engineering viruses to inflame the tumour and improve cancer treatment,” says Workenhe. “The implications of these findings for human cancer therapy may be huge.”

This post was adapted from a University of Guelph news story.

December 1, 2020

Consortium secures $5.1 million to expand genomics platform for COVID research

A national consortium including the Ontario Institute for Cancer Research will expand development of a software platform for genomics and health data and apply it to COVID-19. The $5.1 million project, called COVID Cloud, is co-funded by Canada’s Digital Technology Supercluster and aims to increase Canada’s capacity to harness exponentially growing volumes of genomics and biomedical data to advance precision health. The platform will be used by data scientists and domain experts to help understand, predict, and treat COVID-19 with molecular precision. With a global death count of over 1.4 million people and record numbers of cases nationally, solutions that can help Canada respond to ongoing challenges of the pandemic are urgently needed.

“We are proud to continue to support this consortium’s groundbreaking work through our COVID-19 program,” said Sue Paish, CEO of the Digital Technology Supercluster. “This project shows how Canadian partnerships across multiple organizations and sectors can drive innovation, help us address global health issues, showcase Canadian expertise, and position us well to rebuild and grow our economy.”

The project — a collaboration between BioSymetrics, Centre of Genomics and Policy at McGill University, DNAstack, FACIT, Genome BC, Mannin Research, McMaster University, Microsoft Canada, Ontario Genomics, Ontario Institute for Cancer Research, Roche Canada, Sunnybrook Research Institute, and Vector Institute — brings together Canadian leaders in software engineering, artificial intelligence, cloud computing, genomics, infectious disease, pharmaceuticals, commercialization, and policy. It leverages past work of partners to address needs of infectious disease research with guidance from domain experts.

“Tools that allow us to interrogate SARS-CoV-2 at a molecular level are essential to addressing this global health crisis, both now and in the future,” said Dr. Samira Mubareka, a microbiologist and infectious diseases physician at Sunnybrook, whose team was one of the first in Canada to isolate the novel coronavirus. “The insights we will learn by analysing integrated datasets using technology platforms like COVID Cloud can increase our preparedness for future waves and outbreaks.” Dr. Mubareka will co-chair the project’s translational science efforts along with Dr. Gabriel Musso, Chief Scientific Officer for BioSymetrics. “The infrastructure developed by this initiative will propel collaborative Canadian drug discovery efforts for COVID-19,” said Musso, whose team will lead bioinformatics and computational drug discovery for the project.

A major goal of the project is to make it easy for producers of genomic and health data to share data responsibly over industry standards, and for researchers to harness the collective power of information shared through them. The project deliverables include a suite of software products powered by enterprise-grade implementations of standards developed by Global Alliance for Genomics & Health (GA4GH), protocols that are being designed to facilitate the responsible sharing of genomic and health data, which will help advance precision medicine initiatives around the world.

“The platform is being built on a foundation of open standards that will allow for distributed networks of genomics and biomedical data to be built,” said Dr. Marc Fiume, CEO at DNAstack, whose team will lead software engineering for the project. “We are excited to see these technologies breaking down barriers to data sharing, access, and analysis and create new opportunities for genomics-based discoveries for our partners.”

This project is responding to global demand for highly specialized, scalable, distributed software infrastructure to support collaborative genomics research — a need that has surged since the onset of the COVID-19 pandemic. “COVID-19 has accelerated digital transformation of many industries, especially in healthcare,” said Kevin Peesker, President of Microsoft Canada. “The incredible power of Cloud applied to COVID at scale is expanding development of an information superhighway to securely connect scientists in Canada and around the world to the data and compute power they urgently need to help us overcome one of the greatest global health crises of our time.”

The platform will be used to support a series of projects in partnership with Canadian academic, clinical, and pharmaceutical collaborators, which are being coordinated by Canadian genome centres, Genome British Columbia and Ontario Genomics. These initial projects are being prioritized based on urgency and potential impact on Canada’s response to the COVID-19 pandemic.

“The COVID Cloud is an incredible platform that brings together resources and capacity to enable timely and comprehensive genomic analysis of SARS-CoV-2 for our province and our country,” said Bettina Hamelin, President and CEO of Ontario Genomics, whose team leads the ONCoV Genomics Coalition. “This made-in-Canada solution will immediately accelerate Canada’s response to COVID-19, while being a technological springboard for translating genomic data analysis into actionable medical insights across other disease areas in years to come.”

For more information, visit dnastack.com/solutions/covid-cloud.

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