OICR Annual Report 2018/19

We are pleased to present the Ontario Institute for Cancer Research (OICR) Annual Report for 2018/19.

Translating cancer research means bringing the best research discoveries to patients, and it’s at the heart of the work we do. OICR collaborates with researchers across Ontario and around the world to ensure Ontario’s most significant cancer research discoveries have maximum impact for patients and the province’s economy. This report highlights a selection of OICR’s many translational research successes over the last year, including:

An unprecedented investigation into the dark matter of the human cancer genome, which discovered the causes of two thirds of cancers that were previously unexplained;
A study that’s bringing next generation genomic sequencing to five Ontario cancer centres, helping match patients to targeted therapies and accelerating cancer research;
Developing new software technologies to help bring portable nanopore sequencing into cancer research and care;
A pan-Canadian initiative changing the landscape of lung cancer radiotherapy clinical trials and providing more treatment options to patients;
The scientific and business excellence of Fusion Pharma Inc., which is developing innovative medical isotopes for treating cancer with reduced side effects.

We hope you enjoy learning more about OICR’s many achievements over the past year and we welcome your feedback at info@oicr.on.ca.

Read the report

Hamilton study discovers new approach to target cells at the root of leukemia

Dr. Kristin Hope, Principal Investigator at McMaster University’s Stem Cell and Cancer Research Institute and OICR Investigator.

McMaster University researcher and OICR Investigator, Dr. Kristin Hope, turns her stem cell discovery into a new treatment approach for leukemia.

A few years ago, Dr. Kristin Hope and her research team discovered a new way to grow rare life-saving blood stem cells. Now, the Hope Lab is using this discovery to suppress leukemic stem cells – the cells at the “root” of leukemia.

In their most recent study, published earlier this month in Cancer Research, the Hope Lab discovered that the same molecular pathway they found previously could be turned off to grow healthy stem cells could be turned on to impair the development of cancer stem cells.

The study suggests that this pathway, called the aryl hydrocarbon receptor (AHR) signaling pathway, could be leveraged as a potential therapeutic approach for acute myeloid leukemia – one of the most common subtypes of leukemia.

“We saw a loss of leukemic stem cells by activating – or turning on – the AHR pathway,” Hope says. “This brings us a step closer to a potential new therapy for patients with leukemia.”

The study group used a small molecule to activate the AHR pathway, finding that it had a significant effect in eliminating leukemic stem cells, but no effect on healthy cells. The group found similar results in cell cultures as well as in mice that were transplanted with human leukemia cells.

Hope, who is a Principal Investigator at McMaster University’s Stem Cell and Cancer Research Institute, will continue investigating this small molecule as a potential drug that could complement chemotherapies in the future.

“We will continue building on our understanding of the AHR pathway and how to control it,” she says. “This understanding will help us in the development of new therapies so that our discoveries can one day help patients.”

When the tools you need don’t exist, create them

Dr. Ina Anreiter joins OICR as a Schmidt Fellow, bringing her background in behavioural genetics to bioinformatics

While writing her doctoral thesis, Dr. Ina Anreiter realized that there was a missing piece to her research. What she didn’t realize was that this missing piece would lead her into a prestigious postdoctoral fellowship in an entirely new scientific discipline. For decades, scientists have known that RNA – often referred to as DNA’s cousin – undergoes chemical modifications before running its course. These modifications, like RNA methylation, have an important effect in cancer cells, but without the tools to study RNA modifications, progress in this field had stalled for many years.

Recently, the study of these modifications – also known as the field of “epitranscriptomics” – has garnered new attention as the research community develops new methods to study RNA. These methods, Anreiter says, still rely on common chemistry lab techniques and cumbersome procedures that make studying RNA methylation difficult, especially in application to diseases like cancer.

“I found myself in need of a tool,” says Anreiter. “I needed a way to easily analyze RNA methylation across large datasets and found that nothing existed – well, nothing existed yet.”

From fruit flies to machine learning

Anreiter’s doctoral research focused on the behaviour of fruit flies, specifically how inherited characteristics and environmental factors influence their feeding patterns. While searching for a way to study RNA methylation, her background led her to a unique idea.

Anreiter knew of nanopore sequencing – a relatively new type of sequencing technology that could decode DNA and RNA as it passes through a tiny channel. By directly reading a strand of RNA, Anreiter says, nanopore sequencing has the potential to revolutionize how we study RNA modifications. To this day, however, there are no algorithms or tools that can accurately find RNA methylation patterns in the output data of a nanopore sequencer.

Anreiter had also heard of Dr. Jared Simpson’s breakthrough methods for detecting DNA methylation using nanopore sequencing. His computational methods allowed the nanopore community to sequence the entire – highly-methylated – human genome in 2017, and since, he has been working in part to study RNA modifications, like RNA methylation, using nanopore sequencing.

Anreiter pitched her idea to Simpson.

“RNA methylation occurs in normal fruit flies, but not in a certain type of mutant fly,” says Anreiter. “I had a crazy idea that we could sequence both of these types, and use the datasets to develop a machine learning algorithm that could find RNA methylation on its own.”

The potential of her idea would win her the prestigious Schmidt Science Fellowship and a $100,000 USD stipend to work with Simpson for a year.

From machine learning to cancer patients

Anreiter recently began her year-long postdoctoral fellowship in the Simpson Lab at OICR where she is working alongside a team of computational biologists to turn her idea into an algorithm. She is cross-appointed with the University of Toronto’s Department of Computer Science.

“At this point, we’re working on a preliminary dataset, but I’ve already learned so much. The team has been very welcoming and supportive and we’re working together to make better tools to understand diseases.”

The Schmidt Fellowship, which was co-founded by the former CEO of Google, is awarded to exceptional, early-career researchers making a “pivot” in their work. Anreiter saw the fellowship as an opportunity to immerse herself in a completely new field.

“If we can develop this tool, it would allow us to study human diseases in a new way,” Anreiter says. “When we look at a problem in a new way, we don’t know what solutions we’ll find, but this angle could lead us to new cures.”

Read the UofT News release on Anreiter’s award.

OICR welcomes new investigator, Dr. Parisa Shooshtari

Dr. Parisa Shooshtari, OICR Investigator and Assistant Professor in the Schulich School of Medicine and Dentistry at Western University.

OICR is proud to welcome Dr. Parisa Shooshtari as an OICR Investigator.

Shooshtari specializes in developing computational, statistical and machine learning methods to understand the biological mechanisms underlying complex diseases, like cancer and autoimmune conditions. She is interested in uncovering how genes are dysregulated in complex diseases by integrating multiple data types and applying machine learning methods to analyze single-sell sequencing data.

Of her many achievements, Shooshtari developed a computational pipeline to uniformly process more than 800 epigenomic data samples from different international consortia. She then built and led a team that developed a web-interface and an interactive genome-browser to make the database publicly available to download and explore.

Shooshtari joins the OICR community with research experience from Yale University and the Broad Institute of MIT and Harvard. She also served as a Research Associate with the Centre for Computational Medicine at the Hospital for Sick Children (SickKids).

Shooshtari recently became an Assistant Professor in the Schulich School of Medicine and Dentistry at Western University, where she officially began her career as an independent researcher. Here, Shooshtari discusses her commitment to collaboration and her transition to professorship.

Your work spans multiple disease areas from autoimmune diseases to cancer, what do these diseases have in common? Is there a specific disease that you’re more interested in?

My work focuses on complex diseases, where instead of one gene causing the disease, there are sometimes tens or hundreds of genes working together to give rise to an ailment.

When it comes to complex diseases, we also know that there are multiple factors that we need to consider, including genetics, epigenetics and environmental factors. We live in an era where we have rich datasets with many different types of data. Each of these data types sheds light upon a different aspect of the disease mechanism, but we need to integrate these data types to gain a comprehensive understanding of how a complex disease works.

I develop computational methods for integrative analysis, so complex diseases are definitely the most interesting to me. I feel lucky to be a researcher at this time when I can help bring these data types together to understand mechanisms of diseases, which in turn will help inform treatment selection or help find new therapeutic strategies.

I am interested in applying our data integration methods to several complex diseases but I am currently working with a few Canadian groups to help better understand Diffuse Intrinsic Pontine Glioma (DIPG) – a type of fatal childhood brain cancer.

Your current collaborators include researchers from Yale, Harvard, MIT, SickKids and other leading organizations. How did you initiate and sustain these collaborations?

At the beginning of my research career, I would reach out to scientists who were working on interesting, challenging and cutting-edge problems. I enjoy working in collaborative environments because I believe the key to success in biomedical research is through collaborations between researchers from diverse backgrounds.

With the support of my collaborators, I’ve been able to learn and shift my focus from theoretical computational sciences to applications of data science in genetics of complex diseases. Now, sometimes collaborators approach me with their rich data, which I’m eager to help analyze.

With your new appointment, what are you looking forward to over the next few years?

I am eager to continue expanding my research program and working with new scientists on exciting cutting-edge problems in genetics and epigenetics of complex diseases. New technologies have revolutionized how we study diseases, and we are transitioning to a point where these new technologies are revolutionizing how we treat diseases. I am confident that we will have better ways of treating these diseases in the future using personalized medicine, and I want to help make that a reality.

Visit Dr. Shooshtari’s OICR website page

Addressing high priority issues in cancer care

OICR and Cancer Care Ontario’s Health Services Research Network releases the 2019 Synthesis Report, summarizing 14 studies that address high priority issues in cancer care

An excerpt from the foreword by Drs. Christine Williams and Eva Grunfeld:

Optimal cancer care across Ontario cannot be solely provided by a clinician or implemented by a researcher, enacted by a policy maker or attained by a patient. To improve the delivery of cancer services, we need to work together with stakeholders from across our rich cancer care ecosystem and involve them in prioritizing concerns, designing interventions and implementing solutions. For these reasons, OICR and Cancer Care Ontario (CCO) teamed up to co-create the OICR-CCO Health Services Research Network (HSRN).

Now, a decade later, we present our second Synthesis Report with an additional 14 studies that have emerged from this network. These studies have addressed high priority issues in cancer care including the gap in follow up after a positive colorectal cancer screening test, and the challenges that cancer patients face with co-existing chronic conditions like diabetes. The studies have led to the development of new methods to determine the burden of cancer in Ontario, and new resources to facilitate health services research across the province. This report provides summaries of these studies and others and their impact to date.

How do cancer patients help future cancer patients? This is Ron’s story

The Canadian Cancer Clinical Trials Network launches new pilot project at Windsor Regional Hospital to help patients understand their treatment options and access current clinical studies

In early 2012, Ron Truant, the former Board Chair of Windsor Regional Hospital (WRH), became a patient when he was diagnosed with pancreatic cancer.

Facing a disease with a dismal prognosis, Ron and his wife, Noella Truant, made an appointment for a second opinion at a hospital outside of Windsor. It was there that the Truants learned about an open clinical trial and secured the study’s last available spot.

Noella says not everyone is as fortunate as they were.

“We were lucky to gain access to an immunotherapy trial, which – in combination with a new chemotherapy treatment – gave us another four years together,” says Noella. “Throughout his own treatment, Ron was always thinking about others and realized there were many others who weren’t as fortunate as we were to find a trial. He knew that trials are complex and not everyone can navigate them, so he saw an opportunity to help.”

Last year, only eight per cent of cancer patients in Ontario were recruited to clinical trials and in community hospitals, like WRH, that number drops to fewer than two per cent. These statistics, Noella says, indicate that patients are missing opportunities to gain access to new treatment options and contribute to clinical research.

Currently, each cancer centre in Ontario has a clinical research team that recruits patients for available trials at their respective sites but patients, like Ron, often want to explore all treatment options, including those at other nearby hospitals. These patients and their care givers are frequently left to research trials on their own through websites that may not contain current information or online trial databases that may be difficult to navigate. Even if a patient finds an available trial, understanding eligibility criteria requires specialized knowledge and advanced medical literacy.

Ron, a long-standing advocate for the quality of patient care, teamed up with Dr. Caroline Hamm, an oncologist at the WRH, to develop a better way for patients to navigate clinical trials.

“We want to make sure patients are offered the best treatments available for their individual needs, and that requires more than a database of trials,” says Hamm, who is also the Director of the Windsor Cancer Research Group. “There are many considerations that a patient weighs when deciding to participate in a trial and we need a more considerate approach to help patients with these decisions.”

With support from the Canadian Cancer Clinical Trials Network (3CTN), Hamm and the Truants designed a program where a designated clinical trials specialist – a Clinical Trials Navigator – would help patients find and understand the trials available. A patient could refer themselves to the navigator or they could be referred to the navigator by their oncologist. After reviewing the patient’s case and considering their preferences, the navigator could then identify available trials for which the patient is likely eligible, and help facilitate the connection between a patient and the study team.

Hamm, in Ron Truant’s legacy, launched the Clinical Trials Navigator pilot project at WRH in January and so far the project has since helped more than 40 patients explore trial options.

The process by which the Clinical Trials Navigator project helps patients find clinical trials that may be of benefit.

Youshaa El-Abed, the project’s navigator, sees the impact of this initiative on patients and their care givers first-hand.

“When a patient comes to us, they’re looking for a trial,” says El-Abed. “But even if there are no trials available for them, the patient – and their loved ones – gain reassurance that they have explored their options.”

Due to growing demand for clinical trial navigation services at other hospitals, the project is now open to receive patient referrals from across Ontario.

Hamm, who has been recognized for her patient advocacy in Windsor, hopes to expand this initiative to new sites as she has in the past for a cancer drug access coordinator program. In addition to helping current patients with cancer, Hamm sees the Clinical Trials Navigator project as a way to accelerate clinical research so patients can benefit from research sooner.

“If we can help patients access trials, we can help trials reach their accrual targets sooner – a win-win for patients and for local clinical research,” says Hamm. “A health system with accelerated clinical research allows us to attract more study sponsors, bringing leading edge treatment options to our hospitals. Ron envisioned this solution and we’re proud it’s in action today.”

Dr. Rola Saleeb on her path to becoming a pathologist

OMPRN grantee and former Transformative Pathology Fellow discusses her recently-awarded faculty appointment with the University of Toronto

Despite research advances in identifying the subtypes of kidney cancer, treatment decisions are often based on the size of a patient’s tumour. Dr. Rola Saleeb, who has been studying kidney cancer for nearly a decade, thinks there’s a better way to make these decisions.

“Each month, more than 500 people are diagnosed with kidney cancer in Canada,” says Saleeb. “These individuals and their oncologists face tough decisions to make about their treatment options and I want to help make that decision easier.”

Saleeb, a former OICR Transformative Pathology Fellow and two-time Ontario Molecular Pathology Network (OMPRN) grantee, has recently become a certified pathologist and faculty member in the Department of Laboratory Medicine and Pathobiology at the University of Toronto.

Throughout her doctoral research, Saleeb developed a classification system that could help pathologists distinguish between aggressive kidney cancers and less aggressive cancers. She says this system could, one day, help spare patients from unnecessary surgery if they don’t have aggressive tumours. Additionally, she says classifying these tumours could enable the development of new therapies for these subtypes.

Now as a certified pathologist, Saleeb is the second Transformative Pathology Fellow to have been recruited to a faculty position. Both former fellows have committed to a career where research and development is central to their practice of pathology.

“Not all pathologists do research,” says Saleeb. “But for me, I feel like I can help more patients if I can help find solutions to unsolved problems.”

Saleeb is currently completing a validation study on her classification system. She looks forward to implementing the system at St. Michael’s Hospital and broadening her research to study the molecular origins of kidney cancers and new kidney cancer prevention strategies.

Canadian Government-Sponsored Collaboration Targets Standardized Cancer Testing

Genome Canada, Ontario Institute for Cancer Research and Thermo Fisher Scientific to focus on pancreatic, prostate and breast cancer

CARLSBAD, Calif. – (July 30, 2019) – Genome Canada, the Ontario Institute for Cancer Research (OICR) and Thermo Fisher Scientific are collaborating to develop a complete solution of targeted next generation sequencing (NGS) assays and analysis software designed to more effectively assess – and eventually improve management of – pancreatic, prostate and breast cancer.

The $6 million, three-year initiative aims to standardize advanced molecular profiling in these disease areas and make the assays commercially available globally. Focusing on rapid genomic diagnostics in pancreatic cancer and targeting treatment in breast and prostate cancers, the partnership builds on previous clinical research between OICR and Thermo Fisher and will inform development of three assays that will be utilized to stratify patients in clinical trials in Ontario and other jurisdictions.

“By supporting research and clinical trials, Genome Canada is helping to put more of Ontario’s innovative cancer diagnostics research into clinical use,” said Dr. John Bartlett, program director, diagnostic development at OICR. “This project has the potential to springboard advanced next-generation sequencing to routine clinical use in Ontario and across Canada.”

Breast and prostate cancer are among the most common types of cancer in Canada, and the country’s five-year net survival rate for pancreatic cancer is only 8 percent. However, there is clear evidence that patient outcomes can be improved with NGS-based testing strategies. A recent U.S. health economics study has shown that advanced cancer patients who received treatment based on NGS testing results experienced double the length of progression-free survival without increasing health care costs.¹

While some solutions analyze only DNA sequences, the new targeted NGS assays will provide comprehensive genomic profiles by simultaneously assessing DNA and expression signatures from RNA to provide significantly more insight into driver mutations. The OICR/Thermo Fisher team will leverage this advantage by supplementing the new assays with unique DNA/RNA stratification biomarkers – specific to pancreatic, prostate and breast cancer – previously qualified by OICR translational researchers.

The collaboration is partly funded with a grant from Genome Canada through the Genomic Applications Partnership Program (GAPP). Genome Canada will contribute $2 million, the highest possible level of funding support, with the balance split between OICR and Thermo Fisher, which will cover development costs and validation activities.

Previous research collaborations led by OICR and Thermo Fisher are already well on their way to impacting cancer treatment in the future. Of particular note is a 2016 study designed to identify mutations and copy number variation changes in breast cancer, and clinical research utilizing the Oncomine Comprehensive Assay, which also supports both the National Cancer Institute’s Adult and Pediatric MATCH trials in the United States.

“OICR is a leader in clinical research, with extensive clinical trials in progress to improve care for patients with pancreatic, prostate and breast cancer,” said Jeff Smith, global lead of NGS precision medicine initiatives, clinical NGS and oncology for Thermo Fisher Scientific. “When OICR approached our team with the idea for this project, we saw it as another exciting for opportunity to bring Thermo Fisher’s proven Ion Torrent technology to clinical laboratories across Canada and to contribute to future improvement of patient care.”

¹ “A Retrospective Analysis of Precision Medicine Outcomes in Patients With Advanced Cancer Reveals Improved Progression- Free Survival Without Increased Health Care Costs,” Journal of Oncology Practice, Vol 13, Issue 2, February 2017

OICR funding for Ontario drug discovery projects will accelerate development of new cancer therapies

The Ontario Institute for Cancer Research (OICR) has selected two new Late Accelerator projects to receive support through its Cancer Therapeutics Innovation Pipeline (CTIP) initiative. The projects, detailed below, will each receive up to $250,000 per year, for up to two years, to advance the development of drug candidate molecules. The projects were selected by an international expert review panel from 18 applications.

By joining the CTIP portfolio, these projects will receive more than just financial support – they will also benefit from the guidance of the Therapeutics Pipeline Advisory Committee, a group of industry and academic experts that provides advice on the scientific and strategic direction of CTIP projects.

“CTIP projects have great potential to improve treatment for patients, promote scientific collaboration and drive investment to Ontario’s biomedical research sector,” says Dr. Christine Williams, OICR’s Deputy Director and Head of Therapeutic Innovation. “These new projects are great examples of the innovative cancer therapeutics research happening in our province. We are excited to add them to CTIP’s portfolio of promising drug candidates and look forward to their progress.”

Funded projects

Identification of kinase inhibitors to block the tumour-promoting activity of YAP/TAZ for cancer therapeutics

Liliana Attisano, Principal Investigator, University of Toronto

Rima Al-awar, Principal Investigator, OICR

Frank Sicheri, Co-investigator, Lunenfeld-Tanenbaum Research Institute

Jeff Wrana, Co-investigator, Lunenfeld-Tanenbaum Research Institute

David Uehling, Co-investigator, OICR

Richard Marcellus, Co-investigator, OICR

Methvin Isaac, Co-investigator, OICR

The highly conserved Hippo pathway is a key regulator of cell and tissue growth. Virtually all solid tumours display pathway disruptions, which drive cancer initiation and progression. Mutations in pathway components are rare, making it unclear how to target the pathway for cancer treatment. This research group has shown that certain kinases are key regulators of the pathway that promotes tumorigenicity and observed that diverse human cancers display elevated levels of these kinases. Kinases are highly amenable to the development of targeted inhibitors; therefore, this project will identify potent and specific inhibitors with the long-term goal of establishing novel cancer therapeutics.

Development of kinase inhibitors for ovarian cancer: A novel first in-class immune-oncology therapeutic agent targeting tumor intrinsic stress states

Rob Rottapel, Principal Investigator, Princess Margaret Cancer
Centre

Tracy McGaha, Principal Investigator, Princess Margaret Cancer
Centre

Rima Al-awar, Principal Investigator, OICR

Methvin Isaac, Co-investigator, OICR

David Uehling, Co-investigator, OICR

Richard Marcellus, Co-investigator, OICR

Ahmed Aman, Co-investigator, OICR

The development of new cancer immune therapeutics has triggered a revolution with the recent advent of diverse strategies that engage the patient’s immune system. This research group has identified a novel kinase target that has the unique property of being both an emergent essential gene in high-grade serous ovarian cancer and a repressor of the innate and adaptive immune system. Additionally, they have demonstrated that target inhibition sensitizes cancer cells to cisplatin – a standard of care chemotherapy drug. This project will work to develop a “first-in-class” dual-action, anti-tumour and immune-oncology kinase inhibitors for ovarian cancer and potentially other cancer types.

Patterns in pancreatic cancer samples lead to better prognostic power

Dr. Sangeetha Kalimuthu, gastrointestinal pathologist at the University Health Network, works in her lab. — Dr. Sangeetha N Kalimuthu, gastrointestinal pathologist at the University Health Network, works in her lab. (Photo: UHN)

University Health Network pathologist teams up with OICR researchers to develop an improved pancreatic cancer classification test that can better predict the severity of the disease

Under a microscope, pancreatic cancer often looks like a haphazard collection of cells with various shapes and sizes, but Dr. Sangeetha N Kalimuthu saw something different.

She had been analyzing hundreds of pancreas resections, which are classified using the current three-tiered staging system – well, moderate and poor – but found that the vast majority of cases fell into the moderate category, offering little information to physicians about how best to treat these patients.

N Kalimuthu, a gastrointestinal pathologist at the University Health Network (UHN), noticed that certain patterns in cell shape matched the molecular profile of tumours with poorer survival for patients. She teamed up with Drs. Runjan Chetty and Steven Gallinger at UHN to see if what she noticed was true. Gallinger is Director of OICR’s PanCuRx Translational Research Initiative.

In a study recently published in Gut BMJ, the study group assessed more than 800 pancreatic ductal adenocarcinoma (PDAC) slides and developed an improved classification method that could help differentiate patients with the most aggressive tumours.

“Our aim was to revise and reappraise the current grading system to find features that correlated with these molecular subtypes,” says N Kalimuthu.

By linking molecular profiles of tumours with their appearance, N Kalimuthu was able to develop a classification method that can be easily integrated into current pathology laboratories.

“Any pathologist in any part of the world can do this,” says N Kalimuthu. “It’s the bread and butter of what pathologists do. It’s fast, cheap and accessible.”

N Kalimuthu also says that this method can be augmented using deep learning methods to reduce turn-around times and variability from one pathology laboratory to another.

“Pathologists have had a long, rich history in their vital roles to diagnose and stage pancreas cancer,” says Gallinger, who is co-author of the publication. “This study is an elegant demonstration of the potential of personalized medicine, with the promise of improved outcomes for our patients.”

Read the full UHN News story here.

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