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.
February 27, 2020
International research group finds leukemia drugs and other small molecules may shrink treatment-resistant lung tumours
Lung cancer is the leading cause of cancer death in Canada and around the world. These fatal cancers often arise as a patient’s tumour cells acquire new mutations and become resistant to treatment but Dr. Igor Stagljar has found a new way to stop these tumours. In fact, he may have found four.
Stagljar’s research group at the University of Toronto is well-known for developing a live drug screening method – named MaMTH-DS – that can test potential cancer-fighting molecules in living cells. In a recent study published in Nature Chemical Biology, he and collaborators used these methods to focus on a common mutation, dubbed C797S, which often arises in lung cancers just months after initial treatment. The group identified four new compounds that could block the effects of C797S mutations with no effect on healthy cells.
“Our new technology allows us to find molecules that could be used against cancers for which no other treatment options are available,” says Stagljar, who is a professor of molecular genetics and biochemistry at the University of Toronto. “The advantage of our method is that we are doing it in living cells, where we have all the other molecular machineries present that are important for signal transduction. Also, the compounds are fished at very low dose, which allows us to test for both permeability and toxicity at the same time.”
Conventional drug screening strategies were not able to detect these compounds but Dr. Stagljar’s approach brought these new promising molecules to light.Dr. Rima Al-awar
Two of the molecules identified have already been approved for patients with leukemia. Motivated by their recent findings, Stagljar and collaborators plan to evaluate the effects of these compounds in patients with lung cancer. The first clinical trial to evaluate one of these drugs – gilteritinib – is expected to launch later this year in Toronto, Canada and Zagreb, Croatia.
The other two molecules will require further research and development before they can be trialed in patients. One of these molecules, known as EMI1, could shut down the mutated cells in a completely new way, leveraging molecular machineries to degrade mutated proteins on the surface of tumour cells. The researchers think that EM1’s complex mechanism of action will make it more difficult for tumours to develop resistance to it.
Stagljar is working with Dr. Rima Al-awar, Head of Therapeutic Innovation and Drug Discovery at OICR, and her medicinal chemistry team to create an improved version of the EMI1 molecule. If proven successful, this molecule could potentially become a new treatment for the estimated 60,000 lung cancer patients worldwide who have the C797S mutation.
“Dr. Stagljar’s novel screening approach has identified these very promising molecules” says Al-awar. “We’re proud to collaborate with him and his group to further advance these molecules and accelerate the stages of experimentation between his discovery and helping those with the disease.”
Al-awar, whose drug discovery team recently brought a molecule for blood cancers into pre-clinical development, will leverage her group’s expertise to refine the molecule and move it into the next stage of development, where its ability to shrink tumours can be evaluated in experimental animal models and eventually patients.
This research was supported in part by the Consortium Québécois sur la Découverte du Médicament (CQDM), Cancer Research Society (CRS), Canadian Institute of Health Research (CIHR), Genome Canada and Ontario Research Fund. Stagljar was recently awarded a Prospects Oncology Fund grant from FACIT, OICR’s partner in commercialization, to develop a related drug screening platform, SIMPL.
This post has been adapted from the original announcement made by the University of Toronto Donnelly Centre.
January 10, 2020
OICR-led international research group develops new open-source software to determine the accuracy of computational methods that can map the genetic history of tumour cells.
A cancer patient’s tumour is often made up of many cells with different genetic traits that can evolve over time. Interest in tumour evolution has grown over the last decade, giving rise to several new computational tools and algorithms that can characterize genetic diversity within a tumour, and infer patterns in how tumours evolve. However, to date there has been no standard way to compare these tools and determine which are most accurate at deciphering these data.
The genetic differences between tumour cells can tell us a lot about a patient’s disease and how it evolves over time – Adriana Salcedo
In a study recently published in Nature Biotechnology, an OICR-led international research group released new open-source software that can be used to judge the accuracy of these novel algorithms.Continue reading – New open-source software judges accuracy of algorithms that predict tumour evolution
July 9, 2018
The BETTER program has been awarded almost $3 million to train primary care providers as prevention experts across Canada
As the number of Canadians at risk of cancer and other chronic diseases continues to grow, so does the need for health professionals to deliver effective disease prevention and screening recommendations.
June 19, 2018
Over the past 10 years, more than 300,000 Canadians have volunteered to be part of the Canadian Partnership for Tomorrow Project (CPTP), a research platform that tracks the development of cancers and chronic diseases in the population over several decades to better understand risk factors.
Researchers from across Canada and the University of Toronto published a manuscript in the Canadian Medical Association Journal last week, marking a culmination of effort from hundreds of Canadian researchers to build the project with support from multiple national and provincial funders.
June 13, 2018
Some common pathogens, like the Epstein-Barr virus (EBV), can turn healthy cells into cancer cells, but it is not well understood how they do so. Better understanding how such pathogens work allows researchers to find new ways to target the pathogen’s disease-causing mechanisms and ultimately find new treatments for certain virus-induced cancers.
Dr. Ivan Borozan, from Dr. Vincent Ferretti’s Lab at OICR, and Prof. Lori Frappier at the University of Toronto are working together to better understand EBV and how it triggers the transformation of normal cells to cancerous cells, also known as oncogenesis. Together, they have identified that a key protein expressed by EBV, BKRF4, is one of the likely drivers behind EBV-induced stomach cancers.
March 29, 2018
Canada’s largest health research platform teams up with University of Toronto to accelerate cancer and chronic disease research
Pictured (left to right): Dr. John Mc Laughlin, Executive Director of CPTP; Cindy Morton, Chief Executive Officer of the Canadian Partnership Against Cancer.; and Dr. Philip Awadalla, National Scientific Director of CPTP.
Canadian Partnership for Tomorrow Project (CPTP) enters a new era of scientific activity under the leadership of newly appointed National Scientific Director, Dr. Philip Awadalla
March 29, 2018 (Toronto) – The Canadian Partnership Against Cancer (“the Partnership”) today announced The University of Toronto’s Dalla Lana School of Public Health will be the new national scientific partner of the Canadian Partnership for Tomorrow Project (CPTP) – Canada’s national population cohort for precision health. This new scientific partner will enable a strong national scientific vision for CPTP and support leading-edge research on the possible causes of cancer and chronic diseases, leading to more made-in-Canada discoveries and breakthroughs. In addition, the University has announced that Ontario Institute for Cancer Research (OICR) will be its strategic partner to deliver the expertise and services needed to lead this key research platform.
December 7, 2017
The link between some viruses and cancer has long been established. Now, researchers like OICR’s Dr. Ivan Borozan are using genomic sequencing to analyze common viruses like Epstein-Barr (also called human herpes virus 4). This knowledge could ultimately be used to develop new therapeutic vaccines to keep these viruses from taking hold in the body and prevent associated cancers from ever developing in the first place.
December 4, 2017
OICR launches groundbreaking Cancer Therapeutics Innovation Pipeline to drive cutting-edge therapies to the clinic
Ten new projects were selected in the pipeline’s inaugural funding round, highlighting Ontario’s strengths in collaboration and drug discovery.
Toronto (December 4, 2017) – The Ontario Institute for Cancer Research (OICR) today announced the Cancer Therapeutics Innovation Pipeline (CTIP) initiative and the first 10 projects selected in CTIP’s inaugural round of funding. CTIP aims to support the local translation of Ontario discoveries into therapies with the potential for improving the lives of cancer patients. The funding will create a new pipeline of promising drugs in development, and attract the partnerships and investment to the province necessary for further clinical development and testing.
“Ontario congratulates OICR on this innovative approach to driving the development of new cancer therapies,” says Reza Moridi, Ontario’s Minister of Research, Innovation and Science. “The Cancer Therapeutics Innovation Pipeline will help ensure that promising discoveries get the support they need to move from lab bench to commercialization, and get to patients faster.”
October 23, 2017
The Toronto Bioinformatics User Group’s (TorBUG) 2017-2018 season continues this Wednesday, October 23 with two presentations that promise to be of interest to anyone involved in bioinformatics. Dr. Quaid Morris, Associate Professor at the University of Toronto (U of T) will present “The Genetic Archaeology of Individual Cancers”. Brendan Innes, a PhD Candidate in the Bader Lab at U of T will cover “Cell types in single-cell RNAseq.”
May 18, 2016
Mr. J. Mark Lievonen, a member of OICR’s Board of Directors, and Dr. Laurence Klotz, a doctor and researcher based at Sunnybrook Health Sciences Centre and the University of Toronto, who has conducted OICR-funded research into prostate cancer, were invested as Members in the Order of Canada at a ceremony in Ottawa on May 13.
May 17, 2016
Dr. Eva Grunfeld named as Chair of new Canadian Institute of Health Research Institutes Advisory Board on Chronic Conditions
The Canadian Institutes of Health Research (CIHR) named Professor Eva Grunfeld as the inaugural Chair of the new Institutes Advisory Board (IAB) on Chronic Conditions. In her role, Grunfeld, Giblon Professor and Vice Chair (Research) at the Department of Family and Community Medicine at U of T, will help determine the future directions of research in chronic disease in Canada.
The management and prevention of chronic diseases in Canada represents one of the biggest challenges to our healthcare system
“It’s a great opportunity to contribute to the development of the new IAB structure – the aim of which is to improve integration across CIHR Institutes,” said Grunfeld, who is physician-scientist and Director of the Knowledge Translation Research Network, Health Services Research Program, at the Ontario Institute for Cancer Research. “Particularly with chronic conditions, it’s important to coordinate and cooperate across disciplines, across health conditions, and across research pillars. I’m looking forward to working with the other IAB chairs, IAB and members, and Institute Directors to impact research on chronic conditions in Canada.”