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"Don't Eat Me"
It's a simple biological message whispered by crafty cancer cells to the immune system as they attempt to spread, grow and avoid destruction.
But the complex work to understand and control that signal, which gives those dangerous cells the power to hide, has taken decades of research to understand. Last year, the story took a new twist when it spurred pharmaceutical giant Pfizer Inc.'s acquisition of Trillium Therapeutics in a US$2.22 billion deal.
The groundbreaking research that led to the deal started at UHN's Princess Margaret Cancer Centre and The Hospital for Sick Children (SickKids).
A key collaboration between scientists at both hospitals focused on the cell signal receptor CD47 and its "Don't Eat Me" axis – research that resulted in the creation of a molecule to shut down the protective mechanism used by cancer cells to evade destruction.
Drs. John Dick, Senior Scientist, and Jean Wang, clinician-scientist, both at the Princess Margaret, and Dr. Jayne Danska, Senior Scientist at SickKids, did biological and pre-clinical research that led to the development of TTI-621, a SIRPα fusion protein that targets the signal receptor CD47, thus bolstering the immune system's ability to destroy cancer stem cells.
TTI-621 became a key technology at the Trillium Therapeutics start-up, licensed with support from
Commercialization at UHN and
Industry Partnerships & Commercialization (IP&C) at SickKidsto commercialize the SIRPα discovery and ensure it could be developed for treatments to help cancer patients. That work drew the attention of Pfizer last year and its desire to ink the deal to buy Trillium with a special interest in the TTI-621 drug development project.
In its announcement that the acquisition had closed late last year, Pfizer touted TTI-621 as "a key immune checkpoint inhibitor currently in Phase 1b/2 development across several indications, with a focus on hematological malignancies."
The company says the molecule is also being tested to evaluate clinical potential in solid tumours.
"Pfizer's decision to buy Trillium Therapeutics is the latest testament to UHN's commercialization expertise guiding early-stage science to maximum societal impact, and is proof of the world-class science that powers our ecosystem here in Toronto," says Mark Taylor, Director of Commercialization at UHN.
'This is a story of real discovery'
"Over a decade ago, our scientists recognized the potential that targeting this pathway could have in cancer and licensed this compound to UHN spinoff Trillium Therapeutics to best steward its development," says Dr. Brad Wouters, UHN's Executive Vice President of Science and Research.
"Today, it's being pursued actively as a new approach for cancer immunotherapies in clinical trials because of its potential to create new treatment options for cancer patients."
But going back to the earliest experiments, success was hardly assured according to Dr. Dick, who is also Senior Scientist at UHN's McEwen Stem Cell Institute and Professor of Molecular Genetics at University of Toronto (U of T).
"This is a story of real discovery," Dr. Dick says. "We ended up in a place that was completely unexpected."
The three scientists collaborated on a painstaking process that took a decade to create the ideal pre-clinical models for their experiments. It eventually yielded the finding that blocking SIRPα signaling in pre-clinical models of leukemia enabled elimination of human leukemia stem cells, a sub-population of tumour cells that are resistant to standard chemotherapy.
Dr. Stephen Scherer, Chief of Research at SickKids, says the strong collaboration between the three investigators as well as between the two institutions' commercialization offices was fundamental to accelerating the research.
"SickKids and UHN are globally renowned for pushing the boundaries of scientific discovery," he says. "Open collaboration throughout the initial innovation process enabled a faster understanding of the underlying science and the visioning of potential clinical applications."
The implication of the work was that if the signaling could be blocked by a therapeutic agent, it would unleash the patient's immune system to destroy the cancer cells. The findings had wide-ranging implications beyond just leukemia treatment.
Further research in the labs of Drs. Dick, Wang and Danska led to the development of a molecule that defeats the inhibitory "Don't Eat Me" signal, unleashing macrophages – a type of white blood cell powering the immune system's disease fighting response – on the cancer cells.
"Our molecule unblinds the immune system so it can attack the aberrant cancer cells and destroy them," says Dr. Wang, who is also a staff hematologist at the Princess Margaret and Associate Professor in the Department of Medicine at U of T.
"Normal cells are much less reliant on this signaling axis because they don't have the abnormal characteristics of cancer cells.
"So when you interrupt that "Don't Eat Me" signal, the immune system tends to see the cancer cells first."
"It's not every investigator that gets a chance to take something from bench to bedside," Dr. Wang adds. "It's very promising."
Collaboration driven by a shared curiosity
The research teams say Pfizer's acquisition of Trillium Therapeutics could help ensure that their work is further developed, advancing to one day realize its full potential as a novel immunotherapy in the treatment of many different cancers.
Dr. Danska says the scientific collaboration between the three investigators was driven by a shared curiosity to find the biology behind a puzzling observation.
"We discussed this curious finding multiple times and decided to use a combination of scientific approaches and novel models we had each developed to find the source," says Dr. Danska, Senior Scientist in the Genetics & Genome Biology Program and Associate Chief, Faculty Development and Diversity at SickKids Research Institute, and Professor in the Departments of Immunology and Medical Biophysics at U of T.
"There were no preconceptions – we followed the results and made the discovery.
"This is a true example of what happens when you address fundamental biology questions in the lab. The rich research ecosystem at SickKids and UHN enabled us to solve the puzzle and demonstrate the therapeutic potential of our discovery and partner with industry to bring it to clinical application."
"I'm hoping that a well-resourced company like Pfizer will be able to take this into all the potential avenues where it might make an impact," Dr. Dick says. "We're talking about products that are useful for patients.
"That's the ultimate goal here."