March 24, 2020
Ovarian and pancreatic cancer researchers join forces to debunk which treatments work for which patients
Ovarian and pancreatic cancer are some of the most challenging cancers to treat but their common characteristics have pointed to new treatments for certain subsets of patients. Drs. Stephanie Lheureux and Grainne O’Kane have teamed up to find out which patients can benefit from these new therapies.
Over the next year, with the support of an OICR Translational Research Initiative (TRI) Collaboration Award, Lheureux and O’Kane will be taking a deeper look into patient tumour samples that have a specific DNA damage repair deficiency, called homologous recombination deficiency (HRD). These tumours are thought to be sensitive – meaning, they can be eliminated – with a certain class of drugs called PARP inhibitors, but it is difficult to predict in the clinic whether a patients tumour has HRD or not. Further, it is difficult to determine whether a patient will benefit from using PARP inhibitors.
Lheureux, who is a medical oncologist specializing in ovarian cancers, and O’Kane, who is a medical oncologist specializing in pancreatic cancers, have set out to perform whole-genome analyses on patients with HRD to find a better way to identify which patients may respond to PARP inhibitors. Both researchers are excited to tap into each other’s expertise.
“Dr. Lheureux cares for many patients facing these challenges,” says O’Kane. “She has deep clinical expertise in this area.”
“Dr. O’Kane and her closest collaborators have excellent expertise in whole genome sequencing and bioinformatics,” says Lheureux. “We’re eager to work together.”
Their analyses may help them understand the biological mechanisms driving HRD and how HRD tumours become resistant to treatment. Their findings may also extend beyond ovarian and pancreatic cancers.
“We want to define the biological response to PARP inhibitors and the mechanism of resistance so that we can help these patients make the best treatment decisions for their specific disease,” says O’Kane.
“We’re motivated to redefine HRD and understand it on a deeper level to help us overcome resistance to treatment and extend the lives of those with these cancers,” says Lheureux.
Lheureux and O’Kane’s collaboration is supported by OICR’s TRI Collaboration Award, a pilot funding stream to support the training of young investigators and encourage collaboration amongst OICR’s TRI teams.
January 13, 2020
Researchers identify five subtypes of pancreatic cancer, uncovering new opportunities for targeted treatment of the aggressive disease
Toronto – (January 13, 2020) Researchers at the Ontario Institute for Cancer Research (OICR) and the University Health Network (UHN) have discovered detailed new information about the subtypes of pancreatic cancer. A better understanding of the disease groups may lead to new treatment options and improved clinical outcomes for this lethal disease.
The study, published today in Nature Genetics, represents the most comprehensive analysis of the molecular subtypes of pancreatic cancer to date. Through detailed genomic and transcriptomic analyses, the research group identified five distinct subtypes of the disease (Basal-like-A, Basal-like-B, Classical-A, Classical-B, and Hybrid) with unique molecular properties that could be targeted with novel chemotherapies, biologics and immunotherapies.
“Therapy development for pancreatic cancer has been hindered by an incomplete knowledge of the molecular subtypes of this deadly disease,” says lead author Dr. Faiyaz Notta, Co-Leader of OICR’s Pancreatic Cancer Translational Research Initiative (PanCuRx) and Scientist at UHN’s Princess Margaret Cancer Centre. “By rigorously analyzing advanced pancreatic cancers – which is the stage of disease that most patients have when they’re diagnosed – we were able to create a framework. This will help us develop better predictive models of disease progression that can assist in personalizing treatment decisions and lead to new targeted therapies.”
The study is based on data from more than 300 patients with both early stage and advanced pancreatic cancer who participated in COMPASS, a first-of-its-kind clinical trial that is breaking new ground in discovery science and personalized pancreatic cancer treatment. COMPASS is enabled by advanced pathology laboratory techniques at UHN and OICR, and next generation sequencing at OICR.
“Most pancreatic cancer research is focused solely on early stage – or resectable – tumours, but in reality, pancreatic cancer is often found in patients after it has advanced and spread to other organs,” says Notta. “COMPASS allowed us to look into these advanced cancers while treating these patients, develop a better understanding of the biology behind metastatic pancreatic cancer, and shed light on the mechanisms driving disease progression.”
Interestingly, the Basal-like-A subtype, which had been difficult to observe before this study, was linked with a specific genetic abnormality. Most of the Basal-like-A tumours harboured several copies of a mutated KRAS gene, also known as a genetic amplification of mutant KRAS. The research group hypothesizes that some of the subtypes arise from specific genetic changes that occur as pancreatic cancer develops.
“This research opens new doors for therapeutic development,” says Dr. Steven Gallinger, Co-Leader of OICR’s PanCuRx, Surgical Oncologist at UHN and Senior Investigator, Lunenfeld Tanenbaum Research Institute at Mount Sinai Hospital. “We look forward to capitalizing on the promise of these discoveries, building on our understanding of pancreatic cancer subtypes, and bringing new treatments to patients with the disease.”
This research was supported by OICR through funding provided by the Government of Ontario, and by the Wallace McCain Centre for Pancreatic Cancer by the Princess Margaret Cancer Foundation, the Terry Fox Research Institute, the Canadian Cancer Society Research Institute, the Pancreatic Cancer Canada Foundation, the Canadian Friends of the Hebrew University and the Cancer Research Society (no. 23383).
June 26, 2019
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.”
May 30, 2019
Meta-analysis of 1,200 patients with pancreatic cancer reveals a new way to identify those with very aggressive tumours who may benefit from alternate treatment approaches
Only half of pancreatic cancer patients who undergo standard chemotherapy and surgery live a year after their initial diagnosis. In the face of these dismal statistics, patients are faced with the challenge of deciding whether they want to proceed with treatment that may have unpleasant side effects. If clinicians could identify patients who would not benefit from standard therapies, they could help these patients make more informed treatment decisions or recommend alternative palliative treatment approaches.
As part of OICR’s Pancreatic Cancer Translational Research Initiative (PanCuRx) team led by Dr. Steven Gallinger, Dr. Benjamin Haibe-Kains recognized that computational modeling can be used to help inform these decisions, but to design a robust predictive model he would need much more data than any individual study had ever collected.
Building the data foundations
Haibe-Kains, who is a Senior Scientist at the Princess Margaret Cancer Centre and OICR Associate, began his investigation with a dataset from PanCuRx – the largest collection of genomic and transcriptomic data on primary and metastatic pancreatic tumours to date. He and his lab then incorporated an additional 1,000 cases of pancreatic tumours from studies around the world that had collected both patient samples and information about how each patient responded to treatment.
“The datasets that we aggregated were a mixed bag of different types of data collected through different profiling platforms by different institutions,” says Haibe-Kains. “We took on the challenge of harmonizing the heterogeneity of these resources which nobody else had done.”
Previously, the Haibe-Kains Lab developed a computational method that could make incompatible transcriptomic data compatible. They had used this method to find four new breast cancer biomarkers to predict treatment response and they recognized that they could apply similar methods to harmonize pancreatic cancer data as well.
The dataset resulting from the harmonization is now the largest pancreatic cancer dataset, and Haibe-Kains has made it freely available for other researchers to use and study through the MetaGxPancreas package.
Making a predictive model
Haibe-Kains and his team set out to develop a computational model that could predict if a patient would survive for a year after their biopsy. They used machine learning techniques to exploit their rich dataset, find common patterns in the genomic data of aggressive tumours, and developed PCOSP – the Pancreatic Cancer Overall Survival Predictor.
“Our approach was to look at how one gene was expressed relative to another and relate that to how long a patient lived after biopsy,” says Haibe-Kains. “That may sound simple, but that means dealing with nearly 200 million pairs of genes, which is a significant amount of data to compute.”
As recently described in JCO Clinical Cancer Informatics, the group refined PCOSP using ensemble learning – the combination of several machine learning techniques to improve a model’s accuracy of predictions.
“PCOSP is actually a combination of hundreds of models and not just one,” says Haibe-Kains. “We tested about a thousand models, selected the models that could predict early death very well and combined them to make a stronger classifier.”
Using prediction to power patient decisions
Haibe-Kains says that as the infrastructure for routine sequencing progresses, PCOSP can be translated into clinical practice to help clinicians determine which patients would not benefit from standard treatment and which may benefit from alternative treatment approaches.
“Pancreatic cancer is a challenging disease but if we can predict the course of the disease, we can give clinicians and patients more information. With that information, they can make more personalized decisions to improve their treatment and ideally, their lives.”
January 25, 2019
Large-scale pancreatic cancer study distinguishes primary from metastatic tumours, uncovering new genomic biomarkers that could help guide treatment selection
Over the next decade, pancreatic ductal adenocarcinoma (PDAC) – the most common type of pancreatic cancer – is projected to become the second leading cause of all cancer mortality. A better understanding of how PDAC changes when it metastasizes – or spreads from the pancreas to other organs – may help researchers find ways to treat the disease more effectively.
A study by OICR researchers and collaborators, published today in Cancer Cell, showed that the cells in advanced pancreatic tumours grow – or cycle – faster than those in early tumours, revealing one of the key reasons that the disease can advance so quickly. OICR’s Pancreatic Cancer Translational Research Initiative, PanCuRx, investigated the whole genomes and transcriptomes of more than 300 PDAC tumours, contrasting cells from primary tumours and cells from metastatic tumours. This distinction may help clinicians advise patients about treatment, whether it be surgery, chemotherapy or radiation.
“Often, a patient’s primary pancreatic cancer recurs after surgery and chemotherapy, and there is limited knowledge of metastases to guide the next course of action. In less common ‘metachronous’ cases, treatment depends on whether the second tumour is new, or if it grew from remnants of a previous tumour,” says Dr. Ashton Connor, chief resident in the General Surgery training program at the University of Toronto and lead author of the study. “In this study, we explored differences between primary and metastatic tumours in the hopes of better understanding the mechanisms of cancer cell spread from the pancreas, and to ultimately inform their treatment.”
Over the last decade, PanCuRx has assembled the largest collection of genomic and transcriptomic data on primary and metastatic PDAC tumours. The initiative continues to collect samples through the COMPASS clinical trial today.
“There have been very few studies of advanced PDAC, so our rich dataset is very valuable to the future of pancreatic cancer research,” says Rob Denroche, bioinformatician, Project Leader of PanCuRx and co-author of the study. “Research groups from Germany, Brazil, Japan and across North America have been interested in the data that we’ve collected and we’re happy to enable their discoveries.”
Through COMPASS, PanCuRx will continue to build on these findings and test if cell progression could be used to inform treatment selection in the clinic.
“This work is foundational to our understanding of advanced pancreatic cancer,” says Dr. Steven Gallinger, PanCuRx Director and Head of the Hepatobiliary/Pancreatic Surgical Oncology Program at UHN and Mount Sinai Hospital. “We look forward to building on this understanding to better inform treatment selection for those with this terrible disease.”
March 6, 2018
VANCOUVER – Canadian pancreatic cancer researchers are joining forces under a Terry Fox initiative bringing new hope for patients with this deadly disease.
“For many years it’s been hopeless from a patient perspective, and we are hoping to help shift this,” says Dr. Daniel Renouf (BC Cancer, University of British Columbia) who, along with Dr. David Schaeffer (UBC, Vancouver General Hospital), is leading a $5-million pan-Canadian, precision medicine initiative recently funded by the Terry Fox Research Institute.
A lack of early detection tests. Few known symptoms. Very limited treatment options. No known biomarkers that can be used to direct therapy. These are among the clinical challenges team EPPIC, short for Enhanced Pancreatic Cancer Profiling for Individualized Care, is tackling over the next five years to improve personalized treatments for patients with pancreatic ductal adenocarcinoma (PDAC), a disease with just a nine per cent five-year survival rate.
January 30, 2018
Early results from COMPASS trial demonstrate benefits of using genomic sequencing to guide treatment for pancreatic cancer
Genomic profiling has allowed physicians to customize treatments for patients with many types of cancer, but bringing this technology to bear against advanced pancreatic cancer has proven to be extremely difficult. OICR’s pancreatic cancer Translational Research Initiative, called PanCuRx, has been conducting a first-of-its-kind clinical trial called COMPASS to evaluate the feasibility of using real time genomic sequencing in pancreatic cancer care. The research team recently reported early results from the trial, which show how they overcame the challenges of genomic profiling specific to pancreatic cancer and gained new insights about the disease.
PanCuRx is focused on improving treatment for pancreatic adenocarcinoma (PDAC), the most common form of pancreatic cancer and the fourth leading cause of cancer death in Canada. The group’s approach centres around understanding the genetics and biology of PDAC to inform the selection of therapies, as well as the development of new treatments.
September 29, 2017
We are pleased to share the Ontario Institute for Cancer Research (OICR) Annual Report for 2016/17.
We are living in an era of unprecedented innovation in cancer research. Recent advances have helped us to better understand cancer and allowed for collaboration on a scale that was previously not possible. This work is happening now and it is happening right here in Ontario.
May 25, 2017
OICR launches five all-star teams of Ontario scientists to tackle some of the deadliest forms of cancer
Great strides have been made in cancer research, but much work remains to develop better treatments for the most lethal cancers and to advance new anti-cancer technologies. OICR is taking on a new approach, building on the success of the Institute’s first ten years and Ontario’s strength in particular cancer research areas. Reza Moridi, Ontario’s Minister of Research, Innovation and Science announced that the Institute is funding five collaborative, cross-disciplinary and inter-institutional Translational Research Initiatives (TRIs) with a total of $24 million over the next two years.
The TRIs will bring together some of the top cancer researchers in Ontario and be led by internationally renowned Ontario scientists. Each team will focus on a certain type of cancer or therapeutic technology. To maximize the positive impact of research on patients, the TRIs all incorporate clinical trials into their design. The TRIs, which were selected by an International Scientific Review Panel, are:
- Acute Leukemia TRI (led by Drs. John Dick and Aaron Schimmer at the University Health Network (UHN))
- Brain Cancer TRI (led by Drs. Peter Dirks and Michael Taylor at SickKids)
- Immuno-oncology TRI (ACTION) (led by Drs. John Bell and Marcus Butler at The Ottawa Hospital and UHN)
- Ovarian Cancer TRI (led by Drs. Amit Oza and Rob Rottapel at UHN)
- Pancreatic Cancer TRI (PanCuRx) (led by Dr. Steven Gallinger at UHN)
The funding will also support Early Prostate Cancer Developmental Projects led by Drs. Paul Boutros and George Rodriguez.
“In just over 10 years, the Ontario Institute for Cancer Research has become a global centre of excellence that is moving the province to the forefront of discovery and innovation in cancer research. It is home to outstanding Ontario scientists, who are working together to ease the burden of cancer in our province and around the world,” said Moridi.
“Collaboration and translational research are key to seeing that the innovative technologies being developed in Ontario reach the clinic and help patients,” said Mr. Peter Goodhand, President of OICR. “These TRIs represent a unique and significant opportunity to impact clinical cancer care in the province.”
— SickKids_TheHospital (@SickKidsNews) May 25, 2017
— UHN (@UHN_News) May 25, 2017
— The Ottawa Hospital (@OttawaHospital) May 25, 2017
May 25, 2017
OICR launches five large-scale Ontario research initiatives to combat some of the most deadly cancers
Toronto (May 25, 2017) – Reza Moridi, Ontario’s Minister of Research, Innovation and Science, today announced the Ontario Institute for Cancer Research is launching five unique, cross-disciplinary, multi-institutional Translational Research Initiatives (TRIs), each focused on a single type of or treatment approach to cancer. With $24 million in funding over two years, the TRIs will bring together world-leading scientists to tackle some of the most difficult to treat cancers and test innovative solutions to some of the most serious challenges in cancer today.
The TRIs build on Ontario’s proven strengths in areas such as stem cells, immuno-oncology, pediatric cancers, genomics, clinical trials and informatics. Working together, the province’s top scientists and clinicians will accelerate the development of much needed solutions for patients around the globe, with a focus on acute leukemia and brain, ovarian and pancreatic cancers. Each TRI includes clinical trials to maximize patient impact.
February 10, 2017
OICR researchers to be part of Cancer Research UK’s Grand Challenge helping to answer cancer’s biggest questions
Toronto (February 10, 2017) – Ontario Institute for Cancer Research (OICR) researchers Drs. Lincoln Stein and Steven Gallinger have been announced as members of one of the first global research teams to be recipients of Cancer Research UK’s Grand Challenge.
The Grand Challenge aims to help overcome the biggest challenges facing cancer research in a global effort to beat cancer sooner.
Stein and Gallinger’s pioneering team will study samples from five continents to understand the DNA damage associated with different cancers, to understand what causes them and if they can be prevented. The project will be led by Professor Mike Stratton at the Wellcome Trust Sanger Institute, Cambridge, with collaborators from France, the U.S. and U.K.
October 27, 2016
Ilinca Lungu, a Research Technician in OICR’s Transformative Pathology Program, talks about her group’s contributions to recent findings from the PanCuRx Translational Research Initiative.
Access to the Transformative Pathology Program’s resources and expertise is available to the research community through Diagnostic Development in OICR’s Collaborative Research Resources Directory. For more information about how you can access these services, visit oicr.on.ca/collaborative-research-resources.