December 9, 2020
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.”
November 30, 2020
Researchers find 3-D structure of the genome is behind the self-renewing capabilities of blood stem cells
OICR-funded researchers open a new path to discover drivers of chemotherapy resistance and cancer relapse
Stem cells have the capability to self-renew and create other types of cells, but not all stem cells are equal. OICR-supported researchers at the Princess Margaret Cancer Centre, Drs. Mathieu Lupien and John Dick, have discovered a new way to distinguish the self-renewing capabilities of stem cells, revealing new ways to study the origins of cancer and cancer recurrence.
In their recently published study in Cell Stem Cell, Lupien, Dick and collaborators identified how some blood – or hematopoetic – stem cells can self-renew but others lose that ability. They found differences in the three-dimensional structure of the genetic information between different stem cell types.
DNA within each human cell, including stem cells, is coiled and compacted in a highly regulated way into structures called chromatin. Depending on how DNA is compacted into chromatin, some regions of DNA are accessible to gene-expressing cellular machinery while some aren’t, influencing how genes are expressed and how a cell may behave. The study group identified that this chromatin accessibility is a key component of a cell’s self-renewing capabilities and “stemness”.
“Enabled by the latest technologies, we found that the pattern of closed – or inaccessible – regions of DNA and the open or accessible regions differ between the long-term self-renewing stem cells and other more mature blood cell populations” says Lupien, Senior Scientist at the Princess Margaret Cancer Centre, Associate Professor at the University of Toronto and OICR Investigator.
The study discovered that the self-renewal capabilities are specifically linked to parts of the genome that bind a protein that is responsible for chromatin folding, called CTCF. As cancer researchers, Lupien and Dick are now applying these discoveries made in normal stem cells to study cancer stem cells. It is thought that if a cancer treatment cannot eliminate the cancer’s stem cells, these surviving self-renewing cells can give rise to recurrent tumours. With a better understanding of cancer stem cells, researchers can investigate the roots of cancer and how to potentially target or manipulate the mechanisms behind self-renewal.
This breakthrough study was made possible by Lupien’s expertise in epigenetics, the field that studies gene expression, Dick’s expertise in stemness and blood development, and the contributions of collaborators and trainees, including Drs. Naoya Takayama and Alex Murison who led the wet lab assays and bioinformatics analyses respectively.
“Understanding how stemness is controlled is key to being able to harness the power of stem cells for cell-based therapies, but also to understand how malignant cells perturb stemness to allow the cancer stem cells to continue to propagate tumor growth,” says Dick, Senior Scientist at the Princess Margaret Cancer Centre, Professor at the University of Toronto and lead of OICR’s Acute Leukemia Translational Research Initiative. “We look forward to furthering our understanding of hematopoiesis and bringing these insights closer to clinical application.”
September 16, 2020
Scientists discover mechanism of bone loss caused by acute lymphocytic leukemia, identify targeted therapy for children
OICR-supported research team discovers new pathway through which leukemia cells damage bone and a treatment that may protect children with leukemia from these effects
Due to remarkable progress in the treatment of pediatric leukemias with multi-drug chemotherapy, upwards of 85 per cent of children with the disease survive. One consequence of this success, is that more than a third of these patients suffer from in-bone fractures and pain during leukemia and for years following their treatment. In a recent study, Ontario researchers at the Hospital for Sick Children (SickKids) have discovered a process by which leukemia cells damage bone and discover that a targeted therapy may be able to prevent this damage.
In their study, published in Science Translational Medicine, the research group discovered that the bone degradation in leukemia patients is triggered by a protein called RANKL on the surface of the leukemic cells interacting with receptors called RANK on the surface of bone-degrading cells. The group showed that a drug, which is similar to one that is currently in clinical trials for other cancers, could specifically block this RANKL-RANK interaction and prevent further bone damage.
“A pan-Canadian study demonstrated that 15 per cent of children display bone fractures at the time they are diagnosed with acute lymphocytic leukemia, or ALL,” says lead author Dr. Jayne Danska, Senior Scientist in the Genetics & Genome Biology program at SickKids and Associate Chief, Faculty Development and Diversity at the SickKids Research Institute. “In addition, standard ALL chemotherapy protocols include corticosteroids which further damage the bone. Survivors of childhood ALL experience fractures and pain, and some cases are so severe that they require a hip replacement in their teenage years. We have discovered one mechanism that contributes to ALL-associated bone damage and a potential way to prevent it.”
To make these discoveries, first author of the study, Dr. Sujeetha Rajakumar, a postdoctoral fellow at SickKids, transplanted ALL cells from patient donors into experimental mouse models to examine the effect of leukemia cells on bone and how to disrupt the RANKL-RANK interaction. This so-called xenotransplantation method was pioneered by Dr. John Dick at the University Health Network’s Princess Margaret Cancer Centre.
Using these animal models, Danska’s group showed that treatment of the ALL-transplanted mice with a protein therapeutic that blocks the RANKL-RANK interaction prevented bone damage despite high number of leukemia cells in the bone compartments.
“There are clinical trials underway to test whether RANKL-RANK antagonists can prevent bone degradation in adults with metastatic prostate and breast cancers,” says Danska, who is also a Professor in the University of Toronto’s Faculty of Medicine. “The data we report in the human ALL transplant model is encouraging because the availability of clinical data with this class of drug can accelerate application of our discoveries to clinical trials in youth with ALL.”
“Children with leukemia sustain unbelievably rigorous and lengthy chemotherapy treatments,” says Danska. “We’re eager to bring our discoveries into clinical trials that may help minimize these painful and life-altering late effects of this disease.”
Danska and study collaborators Drs. Cynthia Guidos and Johann Hitzler of SickKids, and Drs. Mark Minden and John Dick of the Princess Margaret Cancer Centre are members of OICR’s Acute Leukemia Translational Research Initiative (TRI), which partially funded the study.
July 29, 2020
OICR welcomes Dr. Courtney Jones to Ontario’s cancer research community
Starting up an independent research lab in the midst of a pandemic is difficult but Dr. Courtney Jones is up for the challenge. Jones moved to Canada prior to the lockdown and has been gearing up for new experiments since. Now, as an OICR Investigator, she has safely started working in her lab at the Princess Margaret Cancer Centre to find new solutions for the leading cause of leukemia deaths in Canada – acute myeloid leukemia (AML).Continue reading – Q&A with new OICR investigator Dr. Courtney Jones on benefitting patients through research
March 2, 2020
Researchers find the roots of leukemia relapse are present at diagnosis, uncovering clues to new treatment approaches
Despite significant advances in the treatment of acute lymphoblastic leukemia (ALL), the disease often returns aggressively in many patients after treatment. It is thought that current chemotherapies eliminate most leukemia cells, but groups of resistant cells may survive therapy, progress and eventually cause relapse. Dr. John Dick and collaborators have found these cells.
In a recent study published in Cancer Discovery, Dick and collaborators were able to identify and isolate groups of genetically distinct cells that drive ALL relapse.
The cells, termed diagnosis relapse initiating (dRI) clones were found to have genetic characteristics that differ from the other leukemia cells that are eliminated by treatment.
The study, along with a complementary study published in Blood Cancer Discovery, unraveled the genetic, epigenetic, metabolic and pro-survival molecular pathways driving treatment resistance. Together, these papers provide an integrated genomic and functional approach to describing the underlying genetics and mechanisms of relapse for ALL.
Interestingly, the research group discovered that dRI clones are present at diagnosis, opening opportunities to improve treatment up-front, devise drugs that target these resistant cells and prevent relapse from ever occurring.
“Our study has shown that genetic clones that contribute to disease recurrence already possess characteristics such as therapeutic tolerance that distinguish them from other clones at diagnosis,” says Dr. Stephanie Dobson, first author of the study who performed this research as a member of John Dick’s Lab. “Being able to isolate these clones at diagnosis, sometimes years prior to disease recurrence, has enabled us to begin to profile the properties allowing these particular cells to survive and act as reservoirs for relapse. This knowledge can be used to enhance our therapeutic approaches for targeting relapse and relapse-fated cells.”
“Xenografting added considerable new insight into the evolutionary fates and patterns of subclones obtained from diagnosis samples,” says John Dick, who is the co-senior author of the study, Senior Scientist at the Princess Margaret Cancer Centre and leader of OICR’s Acute Leukemia Translational Research Initiative. “We were able to gather extensive information about the genetics of the subclones from our models, which helped us describe the trajectories of each subclone and the order in which they acquired mutations.”
Ordering these mutations relied on the advanced machine learning algorithms designed by Dr. Quaid Morris and Jeff Wintersinger at the University of Toronto.
Research efforts are underway to build on these discoveries and determine how to block dRI clones.
The study was led by researchers at St. Jude Children’s Research Hospital, the Princess Margaret Cancer Centre and the University of Toronto and supported in part by OICR’s Acute Leukemia Translational Research Initiative.
This post has been adapted from the St. Jude Children’s Research Hospital news release.
July 3, 2019
The Lebovic Fellowship program connects scientists in Israel and Ontario, leading to the validation of a new drug candidate for leukemia and the optimization of a new potential cancer vaccine
Three years ago, the Institute for Medical Research Israel-Canada (IMRIC) received a donation from Joseph and Wolf Lebovic – two brothers who are Holocaust survivors, Canadian immigrants, avid philanthropists and recently-appointed Members of the Order of Canada. Their vision was to strengthen collaboration between the outstanding researchers in Israel and those in Ontario to accelerate cancer research.
They created the Joseph and Wolf Lebovic Fellowship Program, which paired together laboratories specializing in complementary subjects. The Program’s first round of projects officially came to a successful close today and here we recognize the progress made thanks to the generous donation of the Lebovic brothers.
Developing a drug for leukemia
Israel lead researcher: Dr. Yinon Ben-Neriah, IMRIC
Israel fellows: Waleed Minzel and Eric Hung, PhD Candidates, Hebrew University of Jerusalem
Ontario lead researcher: Dr. John Dick, Princess Margaret Cancer Centre (PMCC)
Ontario fellow: Dr. Laura Garcia-Prat, Postdoctoral Fellow, PMCC
Ben-Neriah’s lab in Israel had developed a new compound and showed it may be a valuable anti-leukemia drug, but they couldn’t explain why the drug was only effective in animal models that had strong immune systems. Understanding the relationship between the drug and the immune system would allow them to validate which leukemia subtypes would respond to their therapeutic approach.
John Dick’s lab had developed the gold standard for evaluating the efficacy of leukemia drugs in animal models using sophisticated patient-derived xenograft mouse models. Through this fellowship, the Ben-Neriah Lab teamed up with the Dick lab to learn from their expertise and gain insights into their experimental models.Continue reading – Five fellows, four labs, three years, two countries, and a generous donation
July 3, 2019
Bridges built between Israel and Canada thanks to philanthropic donation from Joseph and Wolf Lebovic
TORONTO (July 3, 2019) – The Ontario Institute for Cancer Research (OICR), the Institute for Medical Research Israel-Canada (IMRIC) at the Hebrew University of Jerusalem and the Canadian Friends of Hebrew University (CFHU) today honour the successful conclusion of the first round of the Joseph and Wolf Lebovic Cancer Genomics and Immunity Fellowship Program, a cross-continent multidisciplinary collaboration between experts in cancer research. The Program forged two new partnerships between labs in Canada and Israel and provided a unique training opportunity for early career researchers in both countries. These collaborations led to the development of a new potential cancer-killing virus and a new drug candidate for leukemia.
Fellowships were awarded to Adrian Pelin from the lab of Dr. John Bell at The Ottawa Hospital Research Institute, in Ottawa, Ontario and Yoav Charpak Amikam from the lab of Dr. Ofer Mandelboim at IMRIC in Jerusalem, Israel. The collaboration improved the specificity and immune-triggering abilities of the potential oncolytic Vaccinia virus.
Another pair of fellowships were awarded to Dr. Laura Garcia-Prat from the lab of Dr. John Dick at the Princess Margaret Cancer Centre, in Toronto, Ontario and Waleed Minzel and Eric Hung from the lab of Dr. Yinon Ben-Neriah at IMRIC. This partnership enabled the development of leukemia xenograft models to help validate the efficacy of a new drug candidate, as recently published in the scientific journal Cell.
The Lebovic Fellowship Program was established by a philanthropic donation provided to IMRIC by Joseph and Wolf Lebovic – two brothers who survived the Holocaust, immigrated to Canada and have recently been appointed as Members of the Order of Canada for their contributions to the Toronto community.
“We’d like to congratulate the fellows today on their progress which was made possible by the generous support of Joseph and Wolf Lebovic. The funding provided by the Lebovic brothers allowed us to create a platform for Ontario scientists to establish collaborations with researchers in Israel and we look forward to strengthening this platform for future collaborative work,” says Dr. Laszlo Radvanyi, President and Scientific Director of OICR.
“We congratulate the fellows today on their achievements during this first round of the program. IMRIC is proud to continue our collaboration with an institute as distinguished as OICR, supported by the inspiring philanthropy of Joseph and Wolf Lebovic,” says Prof. Haya Lorberboum-Galski, Chairman of IMRIC. “We feel that this collaboration between top Canadian and Israeli researchers will surely lead to significant and game-changing advances in the world arena.”
“Thanks to the vision and generosity of Joseph and Wolf Lebovic, they have been instrumental in creating an international collaboration that will continue to strengthen Israel-Canada connections while benefitting humankind,” says Rami Kleinmann, CEO and President of Canadian Friends of Hebrew University. “CFHU is grateful for their continuing and dedicated support.”Continue reading – Bridges built between Israel and Canada thanks to philanthropic donation from Joseph and Wolf Lebovic
April 18, 2019
OICR is proud to welcome Dr. Sagi Abelson to its Computational Biology Program as a Principal Investigator. Here, Abelson discusses some of his past successes, including his recent leukemia research and his wide range of research interests.
How have you been involved with OICR in the past?
I came to Toronto and joined Dr. John Dick’s lab at the Princess Margaret Cancer Centre as a Postdoctoral Fellow, where I had the opportunity to work with OICR’s Genomics and Genome Sequence Informatics teams. I was investigating the differences between normal aging cells and the cells that lead to leukemia. To do that, we had to look into blood-derived DNA samples from many individuals that develop leukemia following blood collection and search for common genetic markers that indicated a high risk of developing leukemia. I worked closely with OICR teams to prepare and sequence these patient samples. We also collaborated to deploy specialized methodology that enabled us to accurately interpret the genomic data and to identify those harmful mutations.
What motivated you to become involved with that subject?
Far too many patients are diagnosed with leukemia when it is too late. This applies to many other cancers as well. If we can detect a disease earlier, we may benefit from a larger window of opportunity to prevent, manage, or treat the disease. There are many biological and computational challenges that need to be addressed in this area, including finding extremely small traces of a disease amidst a lot of noise in genomic data. I’m interested in the development and the optimization of methods and computational tools to find these first traces of a developing disease.
What will your future research focus on?
In the future I would like to expand my research program to other types of cancers. I truly believe that as a researcher I can achieve more by having a multidisciplinary team that address questions in other biological systems as well. In this era of big data, we are not the only ones realizing that multiple research skills are necessary to tackle the toughest problems. Research institutes and universities understand it as well and therefore introduced computational courses in their biology curricula. That said, conducting research is a team effort and collaboration is the key to approaching scientific problems in areas where you don’t have the expertise.
When approaching the end of your postdoctoral studies and deciding the next step in your career, what opportunities were you considering?
Well, I was looking for a combination of things. I was looking for a place that shares the same vision as I do, the same values of collaboration and translation and a place that has a high caliber of scientists. I believe in the things that OICR works on and how research is done here, so I think it’s a great fit.
What advice would you give to aspiring academics?
To do research well, you first need to love it. You need to be curious, know to identify the needs and ask the right question at the right time. Furthermore, you have to have persistence. You cannot give up in the pursuit of new knowledge.
August 7, 2018
Big data are ushering in a new era of individualized cancer care and prevention, but not without conceptual and practical challenges. Canadian advances in genomics will be made by or limited by bioinformatics analytical capacity as well as the ability to store and analyze data in new and more sophisticated ways.
To help realize the potential of genomics research in cancer, the Canadian Data Integration Centre (CDIC) platform, led by OICR, offers third generation bioinformatics and genomics tools to support both functional and clinical genomics research. CDIC is the largest academic cancer informatics program in the country – offering customizable, client-oriented access services for data challenges across diverse research areas.
July 10, 2018
Acute myeloid leukemia (AML) progresses quickly and requires treatment soon after diagnosis, but the disease begins long before becoming symptomatic. Early indicators of AML were thought to be indistinguishable from healthy aging. But now, an international group of researchers led in part by Dr. Sagi Abelson, a postdoctoral fellow in the lab of Dr. John Dick at the Princess Margaret Cancer Centre, has discovered distinctive traces of AML in patients up to 10 years before they were diagnosed with the disease.
July 11, 2017
The rising use of stem cell-based therapies has illustrated the power of stem cells to treat a number of diseases. Now a group of Ontario researchers are looking at the promise of stem cells from a different perspective. Amongst other efforts, they are developing and testing new therapies that target and kill leukemic stem cells to lessen the chances of acute leukemias (AL) coming back following standard treatment.
June 28, 2017
By combining new knowledge from the fields of stem cell biology and genetics, a group of Ontario researchers led by Dr. John Dick have solved the mystery of why some acute myeloid leukemia (AML) patients relapse after initial treatment.