September 21, 2020
Q&A with new OICR Investigator Dr. Anastasia Tikhonova on tackling cancer cell cross-talk and adapting in a rapidly evolving field
OICR welcomes Dr. Anastasia Tikhonova to Toronto as an OICR Investigator and Scientist at the Princess Margaret Cancer Centre
The pandemic has compelled many people to adapt, and researchers are no exception. For Dr. Anastasia Tikhonova, adapting has always been an essential part of her career.
Tikhonova recently joined the OICR community as an OICR Investigator working at the Princess Margaret Cancer Centre. Her research focuses on hematological malignancies – or blood cancers – and how the environment around these cells can regulate their growth or help them resist standard treatments. Her research in this area will support the development of new cancer therapies that can ultimately help patients live longer and healthier lives.
Here, she describes her research program and why this community is a great place for her.
What is your research all about?
AT: Cancer cells do not exist in isolation. They are surrounded – and influenced – by their healthy neighbouring cells. For a long time, we didn’t fully understand the interactions between a cancer cell and its surrounding environment and how this dialogue impacts tumour growth. The last five years have significantly advanced imaging and genomic technologies that allow us to precisely decode the cross-talk between diseased cells and their environment – or their niche.
This is what my research is all about. My team uses single-cell transcriptomics, high-resolution imaging, and functional genomics to understand the connection between the complex elements in the bone marrow and cancer. Our goal is to untangle these connections and devise new strategies to target the interaction between leukemic cells and their environment, with the goal of eliminating blood cancers.
What got you interested in this space?
AT: I was fascinated by biology as a child. I remember learning about evolution in my first biology class in the fifth grade – I have been hooked ever since! I love being in the lab. I am exhilarated by seeing results for the first time and being able to connect the dots between different experiments. When I recognize a gap in my understanding, I feel compelled to learn more. This is how I became interested in the stem cell niche and leukemic microenvironment. As a Postdoctoral Fellow, I was fortunate to have had the opportunity to work in a top hematopoietic lab where I started to scratch the surface of understanding the niche’s molecular architecture, but many questions remain. Continuing this line of inquiry, I look forward to translating my findings into innovative therapies here in Ontario.
Why did you choose to come to Ontario?
AT: Princess Margaret is one of the top cancer research centres in the world. During my recruitment I had an amazing experience interacting with the faculty and trainees here. They were highly engaged and asked great questions, indicating a rich intellectual environment. Since most of my ideas come to me when I am working with others, this is the ideal place for my young lab to grow intellectually. Plus, the people here are genuinely supportive. My move was delayed due to COVID, but everyone here has been exceptionally helpful.
How has COVID impacted your work?
AT: An important trait to have as a scientific researcher is agility or the ability to quickly adapt to changing environments. Furthermore, COVID made me realize that nothing can shake my enthusiasm for starting a research group.
As a result of pandemic, I think people have become more open to collaboration. In some ways, online communication has leveled the playing field, bringing geographically distant researchers into the same space as colleagues accustomed to side-by-side interactions.
I also think COVID has brought science into public view. For the first time in my life, I hear immunology terms on the morning news. I’m excited by the prospect of biomedical research being a common discussion topic.
Does your work apply to other diseases?
AT: Yes, it does. I have a specific focus in a rare form of leukemia, called T-ALL. My research applies to other cancers as well. Insights from one disease can often guide our understanding of other malignancies.
Notably, my research in the regenerative medicine space of the bone marrow niche has the potential to impact thousands of patients treated every year with bone marrow transplantation. Additionally, if we can better understand how to regenerate the bone marrow microenvironment, we could bring a whole new treatment paradigm to patients with a wide spectrum of benign and malignant diseases. At the end of the day, this is what it’s all about.
September 10, 2020
OICR-supported researcher Dr. Harriet Feilotter leads liquid biopsy research program
As the COVID-19 pandemic has impacted many areas of life, including the diagnosis and treatment of other health conditions, people have chosen to forgo cancer screening and care in attempt to minimize their potential exposure to the virus. Relative to the general population, people living with cancer are more susceptible to the virus, but delaying cancer treatment may allow the disease to grow or spread.
Dr. Harriet Feilotter has teamed up with members of the pan-Canadian Digital Technology Supercluster to bring greater access to cancer testing and treatment during the pandemic and beyond. Through the $2.59 million Project ACTT (Access to Cancer Testing & Treatment in Response to COVID-19), they aim to provide liquid biopsy solutions, which require only a simple blood draw, as alternatives to surgical tissue biopsies for cancer diagnosis and care.
“The goal is to allow patients alternatives to invasive procedures that may be difficult to access during a pandemic,” says Feilotter, Molecular Geneticist and Scientist at Kingston Health Sciences Centre, faculty member of Queen’s Cancer Research Institute and OICR Associate. “Not only would this benefit those patients who live far from large cancer centres, but it could limit patient exposure to COVID-19 and increase health system capacity.”
The collaborative team is led in part by Canexia Health, which develops specialized cancer genomic assays, and Patriot One Technologies Inc.’s subsidiary Xtract AI, which specializes in machine learning solutions across a variety of applications, among other private and public partners. Together, they will work to enhance their current tests that detect mutations in circulating tumour DNA (ctDNA) from blood and deploy these tests for multiple cancer types across Canada.
Now through ACTT, some patients have access to these tests in British Columbia, Ontario, Quebec and Saskatchewan. The long-term objective is to increase access across the country.
“The development of liquid biopsies and ctDNA testing has been accelerated by this pandemic,” says Feilotter. “We’re proud to team up in this cross-disciplinary, cross-sector collaboration to bring these promising solutions to more patients.”
August 28, 2020
In the most comprehensive analysis of whole cancer genomes to date, OICR researchers identify novel sex-linked genomic differences that may be able to predict cancer severity and response to therapy
Cancer differs in males and females but the origins and mechanisms of these differences remain unresolved. A better understanding of sex-linked differences in cancer could lead to more accurate tests and allow sex to be included as a consideration when personalizing treatments for patients.
In a study, published in Nature Communications, OICR’s Constance Li and collaborators identify key genetic characteristics that differ between sexes. Here, Li describes what they found and what this means for patients.
Some studies have already hinted that cancer genomes differ between males and females. What is new about this study?
Previous studies focused on the exomes of patient tumours. That means that they were only looking at a small fraction of the genome that codes for proteins. This study allowed us to look at the entire genome – all of our DNA code – and take a dive deep into many aspects of the disease, like how tumours evolve over time.
By looking at the entire genome and in this ‘dark space’ that we hadn’t explored, we were able to confirm some previous findings but also find new differences between male and female tumour samples.
What sort of differences did you find?
We catalogued the differences we found across nearly 2,000 patient tumours representing more than two dozen different cancer types. Interestingly, we found that biliary cancers – like some liver, gall bladder and bile duct cancers – evolve differently in males than they do in females.
We also found that mutations in the TERT promoter – which is a hot topic in cancer research – occur much more often in men than in women, especially in thyroid cancers.
What does this mean for researchers who are looking into this subject?
Our findings suggest that there are underlying biological differences in the way that male and female tumours begin and progress. Overall, we need to be aware of these differences and consider the sex differences as we develop new tools that can match patients to appropriate treatments.
How else could this be helpful for cancer patients?
These findings are preliminary but powerful. It is important to note that more clinical data and research are needed to validate the differences we found. Ultimately, if we look deeper and find that a cancer progresses along one course in females and a different course in males, we can design roadblocks – or therapies – to stop the cancer along that specific course for that sex.
This paper is part of the Pan-Cancer Analysis of Whole Genomes Project. Read more about the Pan-Cancer project here.
August 25, 2020
OICR-supported researchers demonstrate new drug may eliminate triple negative breast cancer cells in certain patients, discover a new method to identify which patients will benefit
Adapted from UHN’s Media Release.
Triple negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that often spreads to other organs and accounts for one in four breast cancer deaths. OICR-supported researchers at the University Health Network’s Princess Margaret Cancer Centre are zeroing in on the molecular mechanisms that fuel this deadly cancer’s runaway growth to develop more effective treatments for this disease.
In their study, recently published in Nature Communications, they found a promising approach that could potentially identify the patients who could benefit from a more precise, targeted therapy for TNBC.
“This disease has no precision medicine, so patients are treated with chemotherapy because we don’t have a defined therapeutic target,” says co-lead of the study Dr. Mathieu Lupien, Senior Scientist at the Princess Margaret Cancer Centre and OICR Investigator. “Initially, it works for some patients, but close to a quarter of patients recur within five years from diagnosis, and many develop chemotherapy-resistant tumours.”
“These savage statistics mean that we must improve our understanding of the molecular basis for this cancer’s development to discover effective, precise targets for drugs, and a companion test to identify which patients are most likely to benefit the most from such a therapy.”
The study investigated how TNBC cells are dependent on a specific protein called GLUT1 and its associated molecular pathways. Prior studies suggested that TNBC cells were dependent on GLUT1, but this study is the first to demonstrate that blocking GLUT1 function may be an effective therapeutic strategy for certain patients with TNBC.
Using a collection of cell lines, the researchers found that blocking this pathway with a drug-like chemical compound “starved” the cancer cells, but only in a subset of TNBC patient samples. The group investigated further and found a common trait between the cell lines that were sensitive to the drug – they had high levels of a protein called RB1. This indicates that patients with TNBC and high levels of RB1 may, one day, benefit from this drug.
“Having access to diverse cell models of triple-negative breast cancer allows us to distinguish where the potential drug will work, and where it won’t,” says Lupien. “Without this broad spectrum of samples, we might have missed the subset of triple-negative breast cancers that respond to our compound.”
Collectively, this study suggests that clinical evaluation of targeting GLUT1 in certain patients with TNBC is warranted.
“The more we understand about the molecular complexity of cancer cells, the more we can target with precision,” says co-lead of the study Dr. Cheryl Arrowsmith, Chief Scientist for the Structural Genomics Consortium Toronto laboratories and Professor of Medical Biophysics at the University of Toronto. “And the more we can build up a pharmacy of cancer drugs matched to specific changes in the cancer cell, the greater the chance of a cure.”
Read UHN’s Media Release.
July 24, 2020
OICR research leads to new pancreatic cancer clinical trial with aim to change the standard of care for patients
New pancreatic cancer trial, NeoPancONE, launches across Canada
Adapted from Pancreatic Cancer Canada’s press release.
OICR’s PanCuRx team and collaborators have launched NeoPancONE, a Phase II clinical trial that will evaluate a potentially curative treatment strategy for operable pancreatic cancer. The trial, which is supported by Pancreatic Cancer Canada, will recruit patients at 10 cancer centres across the country to evaluate the effectiveness and feasibility of peri-operative chemotherapy – chemo treatment before and after surgery.
Typically, only 50 per cent of pancreatic cancer patients receive chemotherapy after surgery due to a range of personal and health reasons. NeoPancONE will help evaluate whether chemotherapy treatment before surgery can help extend the lives of these individuals.Continue reading – OICR research leads to new pancreatic cancer clinical trial with aim to change the standard of care for patients
July 21, 2020
OICR researchers and collaborators awarded $520,000 in new funding for COVID-19 drug discovery project
OICR Scientific Advisor and Group Leader, Dr. Gennady Poda, and collaborators at Sunnybrook Research Institute have been awarded $520,000 to identify new therapeutics and existing drugs that could be repurposed for the treatment of COVID-19. This award, which was announced on July 17 by Premier Doug Ford, is part of the Government of Ontario’s $20 million COVID-19 Rapid Research Fund.
Using OICR supercomputers and advanced computational chemistry techniques, Poda and collaborators aim to identify drugs that can stop the virus from replicating in the body by targeting the virus’ key polymerase enzyme, RdRP.
“We’ll be looking for new potential drugs to treat the COVID-19 infections by rapidly identifying approved drugs and compounds that are in clinical trials that could inhibit RdRP,” says Poda. “We will advance the most promising compounds into preclinical animal models and, if the data is promising, into patients.”Continue reading – OICR Drug Discovery awarded for COVID-19 research
June 26, 2020
OICR’s Genome Informatics team announces international release of the ICGC-ARGO Data Platform, the all-in-one data hub for the largest clinical-genomic data sharing initiative in the world
We’re in the midst of an era of big data that is changing the way we understand the world – including how we study, diagnose and treat cancers.
Improvements in sequencing technology and computational power have allowed us to collect massive amounts of information about cancer patients and their tumours. This information, however, is only powerful if it can be accessed by those who can transform big data into new discoveries.
Over the last decade, OICR’s Genome Informatics has built a reputation for developing robust big data portals that provide cancer data access to thousands of researchers around the world. Now, the Genome Informatics team has set out to do it again – this time with bigger data.Continue reading – Opening the virtual floodgates for cancer research and discovery
June 16, 2020
OICR’s Drug Discovery Program and the Structural Genomics Consortium join Europe’s new large-scale collaboration focused on generating open-access chemical tools for disease research and drug development
Developing a new drug is a long, arduous and expensive process, requiring carefully-designed chemical compounds and the expertise to turn these compounds into medicines. In a massive international effort to accelerate this process, Europe’s Innovative Medicines Initiative (IMI) has recently launched a five-year, €66M, 22-partner consortium, EUbOPEN. OICR is a proud EUbOPEN partner.
Over the next five years, the consortium’s 22 participating organizations are teaming up to develop chemical probes and share those probes openly with the scientific community. Together, they will develop these chemical tool compounds for 1,000 proteins, representing a third of all druggable proteins in the human body.Continue reading – OICR joins European consortium to ‘enable and unlock biology in the open’
June 9, 2020
OICR-supported study finds key mechanisms driving a severe form of brain cancer affecting infants and toddlers
When a young child is diagnosed with ependymoma, their treatment options are limited to surgery and radiation therapy – the latter of which causes severe side effects to the developing brain. Despite several clinical trials, scientists have yet to identify life-extending chemotherapies for this type of brain cancer.
In an OICR-supported study recently published in Cell, a research team at The Hospital for Sick Children (SickKids) re-examined how scientists have been studying ependymoma and invented new ways to model the disease. Their work has uncovered key mechanisms behind these tumours and new approaches to treat them.
Lead authors Dr. Antony Michealraj and Sachin Kumar, who are both members of Dr. Michael Taylor’s lab, discussed these promising findings with OICR News.
What spurred this research question?
AM: Unfortunately, treatment options for young children with ependymoma are very limited. Radiation treatments led to severe side effects and the disease often returns, so we are very motivated to develop new therapies for these infants and toddlers.
Our previous research showed that these brain tumours emerge very early in a child’s development and, remarkably, there are no specific genetic mutations that are known to cause these tumours. Instead, these tumours possess a unique way of regulating what genes are on or off – a unique epigenetic profile.
We observed that patient tumours have an enriched hypoxia (oxygen level) signature which is correlated with poor survival. These unusual scenarios pushed us to study how hypoxia and epigenetics are linked in ependymoma to search for potential solutions.
How did you approach this challenge and what did you find?
AM: The first problem that we faced was the availability of relevant disease models. What we realized was that we could not study the disease unless it was in a very specific environment with fine-tuned oxygen levels. In the body, these cancer cells only grow in low oxygen and we needed to mimic such an environment. Once we did so, we ended up with an exceptional experimental model of ependymoma that nobody has been able to create before.
These models allowed us to study the microenvironment of ependymoma cells. We saw that the cellular metabolism, or how a cell consumes and uses nutrients, was responsible for the epigenetic dysregulation seen in patients. Using an array of metabolic and epigenetic inhibitors, targeting these pathways destroyed ependymomas, providing an avenue for novel therapeutic interventions.
SK: One exciting finding was what we call our “Goldilocks” model. The key was histone lysine methylation – a process regulating how DNA is wrapped and coiled in a cell. Ependymoma cells require a very fine balance of histone lysine methylation, and too much or too little results in the cells dying.
By studying how to keep these cells alive, we learned how we could potentially eliminate them. The idea would be to find or repurpose drugs that target these pathways within the body, creating an unfavorable environment and eliminating them for good.
How can we translate these discoveries into new therapies for patients?
SK: With our new knowledge of the key molecular pathways involved in ependymoma, we can now look to develop specific compounds – or potential drugs – that can alter these pathways, disrupt the cancer cell’s environment, and prevent these tumours from growing. These compounds may include drugs that are already in clinical studies or completely new molecules. What’s great is that now we have a model that we can use to screen these drugs more effectively.
AM: We can screen FDA-approved drug libraries on these disease models which will enable us find potential chemotherapies rapidly. Since there are currently no approved medicines that work for this type of brain cancer, if we find a drug that works, it could potentially become the standard of care for this disease around the world.
We hope that these findings pave the way for future therapy development. Although we’re in the very early stages of developing any new drugs, we understand how important this work is to the children and families affected by the disease. We’re committed to finding new solutions for them.
Read more about our achievements in brain cancer research on OICR News.
May 25, 2020
OICR-funded researchers pinpoint short-lived cells that give rise to childhood brain tumours
Childhood brain tumours are remarkably complex, but understanding their origins could help researchers develop drugs to eliminate them. Where can these cells be found? How early do they appear? How do they lead to tumours? For Dr. Hayden Selvadurai, these unresolved questions were a call to action.
In a recent study, published in Cell Reports, Selvadurai and collaborators at The Hospital for Sick Children (SickKids) discovered a rare type of stem cell that gives rise to medulloblastoma, the most common type of brain cancer in children. Their study shows that these cells arise early in brain development and exist for a brief period of time – a developmental window which scientists can now home in on.
“If we can’t eliminate the stem cells at the root of medulloblastoma, we can’t effectively treat the disease,” says Selvadurai, who was a Postdoctoral Fellow under the supervision of Dr. Peter Dirks while leading this study. Dirks is Head of the Division of Neurosurgery at SickKids, Principal Investigator at The Arthur and Sonia Labatt Brain Tumour Research Centre, Professor at the University of Toronto and Co-leader of OICR’s Brain Cancer Translational Research Initiative (TRI). “These problematic cells arise amid a complex and intricate process of fetal brain development and we were able to pinpoint exactly when that happens.”
The study builds on the research group’s previous publication in Cancer Cell that traced the origins of medulloblastoma growth back to a small group of cells that distinctively expressed the SOX2 gene. Using single-cell RNA sequencing, lineage tracing and advanced imaging techniques, the team showed that these stem cells were responsible for generating all other tumour cells and could give rise to new tumours if not fully eliminated.
“I’m proud of these findings because we were able to unify our knowledge of developmental neurobiology with cancer biology,” says Selvadurai. “We were able to build on our understanding of medulloblastoma growth while improving our experimental models of brain cancer. Together, this work could help the community develop new effective treatments for patients with the disease.”
Dirks’ research group plans to further investigate the genes involved in the early stages of medulloblastoma in collaboration with OICR’s Brain Cancer TRI team.
This study was supported in part by the Canadian Institutes of Health Research and OICR through the Stand Up to Cancer (SU2C) Canada Cancer Stem Cell Dream Team.
May 13, 2020
Toronto researchers unravel key cancer-driving circuit between the “powerhouse” and the “brain” of leukemia cells, in big first step for future therapeutic discovery and development
Over the last few decades, research has suggested that mitochondria, also known as the “powerhouses of the cell”, play an important role in tumour growth and development, but little is known about how to prevent these cellular machines from wreaking havoc. In a recent study, scientists have discovered a key protein that is made in the “powerhouse of the cell”, unexpectedly affects the expression of genes in the nucleus, or the “brain”, of certain leukemia cells. The study was launched by Dr. Dilshad Khan, who – alongside colleagues in Dr. Aaron Schimmer’s lab at the Princess Margaret Cancer Centre – set out to determine which genes in the mitochondria were essential to the growth and viability of acute myeloid leukemia (AML).
Through genome-wide CRISPR screening and other gene-manipulating techniques, they discovered a key mitochondrial protein that AML cells can’t survive without – MTCH2. Their findings, which were recently published in Blood, may eventually lead to new ways to fight this common and fast-growing form of blood cancer.
“We found that the mitochondrial protein MTCH2 is essential for the growth and survival of AML cells,” says Khan, Postdoctoral Fellow in the Schimmer Lab, who is the first author of the study. “But finding this protein was just one piece of the puzzle. We needed to understand how it worked.”
With Khan’s expertise in epigenetics, the team systematically dissected how MTCH2 affects AML cells. They found that blocking this protein would ultimately cause leukemic stem cells – the difficult-to-treat renewable cells that are thought to be at the root of leukemia – to irreversibly transform into cells that are easier to eliminate with existing chemotherapies.
“Through a series of experiments, we unraveled how MTCH2 affects AML cells and discovered that this protein has a remarkable and unexpected impact on nuclear pathways – it could control nuclear gene expression to affect AML stemness and survival,” says Khan. “We never thought this could happen, but now that we’ve discovered these new links, we could potentially find new ways to control these mechanisms.”
Next, the Schimmer Lab and collaborators plan to investigate MTCH2’s specific mechanism to find where inhibitors – or potential cancer drugs – could block its path. These initiatives will add to Schimmer’s research on dysregulated mitochondrial pathways in leukemia, including his recent work on fat production and copper distribution in leukemic stem cells. This research is funded in part by OICR’s Acute Leukemia Translational Research Initiative and OICR’s Cancer Therapeutics Innovation Pipeline.
“This study showed us that mitochondrial proteins are more interconnected with other cellular networks than we thought,” says Khan. “These fundamental findings have shed light on new research avenues that we can pursue to find new solutions that will hopefully benefit patients with AML.”
April 29, 2020
The province’s oncology-specialized research ethics board honours Janet Manzo’s contributions as she retires and welcomes new Executive Director, Natascha Kozlowski
Since 2006, two years after its inception, Janet Manzo has led the Ontario Cancer Research Ethics Board (OCREB) as Executive Director. Through her tireless commitment to research ethics, she has established OCREB as a leading central research ethics board for the province that is also widely recognized across the country for its innovative model and approach to research ethics. Manzo has recently announced her retirement and joins OCREBs members its Advisory Committee in welcoming Natascha Kozlowski to succeed her as Executive Director.
Kozlowski, who is the former Director of Research at Lakeridge Health, a five-site hospital system serving Durham Region, brings nearly two decades of experience in clinical research to OCREB’s leadership team.
We sat down with Manzo and Kozlowski to discuss changes in research ethics since OCREB was established and OCREB’s next chapter.
How have cancer clinical trials and ethics processes evolved in Ontario since OCREB began?
Janet Manzo (JM): OCREB was essentially like a start-up. When it was created, there was no model like it in Canada. OCREB has radically changed the research ethics environment for multi-centre cancer trials in Ontario. Today, OCREB enables research by streamlining the review process, minimizing redundancy in hospitals across Ontario, promoting consistency, and saving time and costs by serving as a specialized, consolidated committee for ethics reviews.
Looking back over these years, it’s clear that cancer clinical trials have become more complex. For example, we’ve seen new and innovative study designs, more and more thorough consent forms, more frequent inclusion of quality-of-life assessments, and increases in biologic specimen collection for biomarker development, genetic testing and future research. I’m grateful to have had the opportunity to lead OCREB operations for more than fourteen years, a period of constant growth and change, leading to a successful and well-respected model of ethics review for multi-centre cancer research.
Natascha Kozlowski (NK): From my experience as the Director of Research at a large hospital, I witnessed – on the ground level – how OCREB positively impacts cancer research at hospitals. I can attest that OCREB has helped improve research ethics processes at sites across Ontario while enabling life-saving, ethically-sound clinical research.
How does OCREB adapt to changes in cancer clinical trials?
JM: For research ethics boards, the increasing complexity of clinical trials means it is more important than ever to stay current and to have the right expertise around the table, such as experts in pathology or genetics. OCREB has and will continue to evolve as new cancer technologies and clinical trial designs emerge.
NK: To echo Janet: new clinical trial designs bring new ethical considerations to the table. I think Janet has set up a tremendous organization with a great network of support – OICR included – that can continue evolving to enable innovative research.
JM: I’d like to thank all of the OCREB staff, advisors and members for their unfailing support and for their steadfast dedication to the protection of research participants. I will miss everyone but I am confident that OCREB is in good hands.
What does the future hold for OCREB? What are you looking forward to the most?
NK: OCREB has a strong history of excellence in the clinical trial environment, often being consulted as a respected source of ethics guidance. I look forward to working with our Members and Advisory Committee in the years to come to uphold and strengthen OCREB’s reputation while advancing cancer research.
I would like to express my sincerest thanks to Janet Manzo for many years of dedication and leadership in building an outstanding research ethics board. Over the years, Janet has earned the trust and respect of OCREB’s many members – including clinicians, researchers, ethicists, privacy experts, and community members – while serving Ontario’s cancer research hospitals and centres. I wish Janet all the best as she begins her retirement.