Princess Margaret Cancer Centre

A preclinical study is revealing new insights into the molecular machinery that drives the aggressiveness of pancreatic cancer.

The ability of pancreatic cancer to invade and spread to other parts of the body is a major factor in its poor prognosis, with an overall five-year survival rate of less than 10 per cent.

“Pancreatic cancer cells are known to be very metastatic and that’s a big problem,” says Leonardo Salmena, an associate professor of pharmacology and toxicology in the ��Ƶ’s Temerty Faculty of Medicine.

Salmena is the senior author of a study, published in the Journal of Cell Biology, that investigates the role of a gene called INPP4B in pancreatic cancer’s ability to spread. Led by post-doctoral researcher Golam Saffi and former master’s student Lydia To, the team found that INPP4B exerts its tumour-promoting effects via a cellular organ called the lysosome.

“Classically, the lysosome is a garbage disposal organelle where old and tired proteins and other organelles get degraded to be used for energy and other building blocks for the cell,” says Salmena.

In most cells, lysosomes typically cluster around the nucleus. But in pancreatic cancer cells, the researchers found that INPP4B drove the lysosomes from the cell interior to the periphery, where these organelles fuse with the cell’s outer membrane. In doing so, the enzymes and other lysosomal factors responsible for breaking down cellular waste are dumped into the space surrounding the tumour cells.

This space contains a network of proteins and molecules that provides crucial structural support to cells and tissues while also restricting a cell’s ability to move. The release of the lysosome’s protein-degrading contents into this extracellular space causes the stabilizing network to fall apart, thus making it easier for pancreatic cancer cells to migrate and invade other tissues.

Crucially, Salmena and his team also identified the signalling pathway by which INPP4B drives the movement of lysosomes to the cell edge. INPP4B works with two other proteins – PIKfyve and TRPML-1 – to modify the lysosome’s surface structure and alter local calcium levels so that the organelle is propelled to the cell periphery.

Based on these findings, the researchers are testing two experimental drugs that target TRPML-1 and PIKfyve in a preclinical model of pancreatic cancer. They are also studying how the release of lysosomal contents can change the immunological environment of the cancer cells, and what effects that might have on the immune system’s ability to respond to the tumour.

Salmena first became interested in INPP4B when, during his post-doctoral research, he found that it was involved in breast cancer. Since then, he and his team have shown that the effects of INPP4B vary depending on the context.

For example, in some breast cancer types, INPP4B behaves as a tumour suppressor whereas it has an activating role in other aggressive cancers like pancreatic cancer – which the Canadian Cancer Society expects to be the third leading cause of cancer death in Canada in 2024, with an estimated 6,100 people dying from the disease.

Salmena and his colleagues later showed that among all cancers, INPP4B levels are highest in pancreatic tumours, and that high levels of the protein are associated with decreased overall survival in people with pancreatic cancer.

The study was a collaboration between Salmena’s group, Roberto Botelho, a professor of chemistry and biology at Toronto Metropolitan University, and Steven Gallinger, a hepatobiliary and pancreatic surgical oncologist and clinician-scientist at Princess Margaret Cancer Centre, University Health Network and a professor of surgery and laboratory medicine and pathobiology in Temerty Medicine. He is also director of the PanCuRx Translational Research Initiative at the Ontario Institute for Cancer Research.

The study was supported by the Cancer Research Society and the Canadian Institutes of Health Research.

Researchers develop new method for delivering RNA and drugs into cells

Christopher.Sorensen — Mon, 16 Sep 2024 15:02:15 +0000

Researchers develop new method for delivering RNA and drugs into cells

Christopher.Sorensen Mon, 09/16/2024 - 11:02

Cutline

PhD candidate Kai Slaughter, left, and University Professor Molly Shoichet are exploring how ionizable drugs can be used to co-formulate small interfering RNA (siRNA) for more effective intracellular delivery (supplied images)

Qin Dai

Topic

Institute of Biomedical Engineering

Donnelly Centre for Cellular & Biomolecular Research

Faculty of Applied Science & Engineering

Subheadline

"This could be a game-changer for treating complex conditions where targeting multiple pathways is beneficial, such as cancer and viral infections"

Researchers at the ��Ƶ and its hospital partners have developed a method for co-delivering therapeutic RNA and potent drugs directly into cells, potentially leading to a more effective treatment of diseases.

The research, published recently in the journal Advanced Materials, explores how ionizable drugs can be used to co-formulate small interfering RNA (siRNA) for more effective intracellular delivery.

The team – including Molly Shoichet, the study’s corresponding author and a University Professor in U of T’s department of chemical engineering and applied chemistry in the Faculty of Applied Science & Engineering – specifically targeted drug-resistant cells with the delivery of a relevant siRNA. The siRNA was discovered study co-author and collaborator David Cescon, a clinician scientist at the Princess Margaret Cancer Centre, University Health Network, and an associate professor in U of T’s Temerty Faculty of Medicine.

“We found that our co-formulation method not only potently delivered siRNA to cells but also simultaneously delivered active ionizable drugs,” said research lead author Kai Slaughter, a PhD candidate in Shoichet’s lab.

“This could be a game-changer for treating complex conditions where targeting multiple pathways is beneficial, such as cancer and viral infections.”

siRNA is a powerful tool in medicine, capable of silencing specific genes responsible for disease, but delivering these molecules into cells without degradation remains a significant challenge. While recent innovations in ionizable lipid design have led to efficiency improvements, traditional nanoparticle formulations are limited in the amount of small molecule drugs they can carry.

When therapeutic formulations are absorbed by cells, small molecule drugs and siRNA are often trapped in small compartments called endosomes, preventing them from reaching their target destination and reducing their effectiveness.

The research team discovered that combining siRNA with ionizable drugs – compounds that change their charge based on pH levels – enhances the stability and delivery efficiency of siRNA inside cells, helping both the siRNA and drug escape the endosome and more effectively reach their destination. This novel method utilizes the protective properties of lipids to safeguard siRNA during its journey through the body and ensure the release of RNA and the drug together within the target cells.

“One of the biggest hurdles in siRNA therapy has been getting these molecules to where they need to go without losing their potency,” Shoichet says.

“Our approach using ionizable drugs as carriers marks a significant step forward in overcoming this barrier, while also showing how drugs and RNA can be delivered together in the same nanoparticle formulation.”

Researchers uncover DNA repair mechanism that could yield treatments for cancer, premature aging

Christopher.Sorensen — Wed, 08 May 2024 14:03:08 +0000

Researchers uncover DNA repair mechanism that could yield treatments for cancer, premature aging

Christopher.Sorensen Wed, 05/08/2024 - 10:03

Cutline

From left to right: researchers Mia Stanić, Razqallah Hakem, Mitra Shokrollahi, Karim Mekhail and Anisha Hundal (photo by Erin Howe)

Erin Howe

Topic

Resarch & Innovation

Laboratory Medicine and Pathobiology

Subheadline

“It’s exciting to think about where these findings will lead us next”

Researchers at the ��Ƶ and partner hospitals have discovered a DNA repair mechanism that advances understanding of how human cells stay healthy – a finding that could lead to new treatments for cancer and premature aging.

The study, published in the journal Nature Structural and Molecular Biology, also sheds light on the mechanism of action of some existing chemotherapy drugs.

“We think this research solves the mystery of how DNA double-strand breaks and the nuclear envelope connect for repair in human cells,” said Karim Mekhail, co-principal investigator on the study and a professor of laboratory medicine and pathobiology in U of T’s Temerty Faculty of Medicine.

“It also makes many previously published discoveries in other organisms applicable in the context of human DNA repair, which should help science move even faster.”

DNA double-strand breaks arise when cells are exposed to radiation and chemicals, and through internal processes such as DNA replication. They are one of the most serious types of DNA damage because they can stall cell growth or put it in overdrive, promoting aging and cancer.

The new discovery, made in human cells and in collaboration with Razqallah Hakem – a senior scientist at UHN’s Princess Margaret Cancer Centre, University Health Network, and a professor in Temerty Medicine’s department of medical biophysics and department of laboratory medicine and pathobiology – extends prior research on DNA damage in yeast by Mekhail and other scientists.

In 2015, Mekhail and collaborators showed how motor proteins deep inside the nucleus of yeast cells transport double-strand breaks to “DNA hospital-like” protein complexes embedded in the nuclear envelope at the edge of the nucleus.

Other studies uncovered related mechanisms during DNA repair in flies and other organisms. However, scientists exploring similar mechanisms in human and other mammalian cells reported little to no DNA mobility for most breaks.

“We knew that nuclear envelope proteins were important for DNA repair across most of these organisms, so we wondered how to explain the limited mobility of damaged DNA in mammalian cells,” Mekhail says.

The answer is both surprising and elegant.

When DNA inside the nucleus of a human cell is damaged, a specific network of microtubule filaments forms in the cytoplasm around the nucleus and pushes on the nuclear envelope. This prompts the formation of tiny tubes, or tubules, which reach into the nucleus and catch most double-strand breaks.

“It’s like fingers pushing on a balloon,” says Mekhail. “When you squeeze a balloon, your fingers form tunnels in its structure, which forces some parts of the balloon’s exterior inside itself.”

Further research by the study authors detailed several aspects of this process. Enzymes called DNA damage response kinases and tubulin acetyltransferase are the master regulators of the process, and promote the formation of the tubules.

Enzymes deposit a chemical mark on a specific part of the microtubule filaments, which causes them to recruit tiny motor proteins and push on the nuclear envelope. Consequently, the repair-promoting protein complexes push the envelope deep into the nucleus, creating bridges to the DNA breaks.

“This ensures that the nucleus undergoes a form of reversible metamorphosis, allowing the envelope to temporarily infiltrate DNA throughout the nucleus, capturing and reconnecting broken DNA,” says Mekhail.

The findings have significant implications for some cancer treatments.

Normal cells use the nuclear envelope tubules to repair DNA, but cancer cells appear to need them more. To explore the mechanism's potential impact, the team analyzed data representing over 8,500 patients with various cancers. The need was visible in several cancers, including triple-negative breast cancer, which is highly aggressive.

“There is a huge effort to identify new therapeutic avenues for cancer patients, and this discovery is a big step forward,” says Hakem.

“Until now, scientists were unclear as to the relative impact of the nuclear envelope in the repair of damaged DNA in human cells. Our collaboration revealed that targeting factors that modulate the nuclear envelope for damaged DNA repair effectively restrains breast cancer development,” Hakem says.

In the aggressive triple-negative breast cancer, there are elevated levels of the tubules – likely because they have more DNA damage than normal cells. When the researchers knocked out the genes needed to control the tubules, cancer cells were less able to form tumours.

One medication used to treat triple-negative breast cancer is a class of drugs called PARP inhibitors. PARP is an enzyme that binds to damaged DNA and helps repair it. PARP inhibitors block the enzyme from performing repair, preventing the ends of a DNA double-strand break in cancer cells from reconnecting to one another.

The cancer cells end up joining two broken ends that are not part of the same pair. As more mismatched pairs are created, the resulting DNA structures become impossible for cells to copy and divide.

“Our study shows that the drug’s ability to trigger these mismatches relies on the tubules. When fewer tubules are present, cancer cells are more resistant to PARP inhibitors,” says Hakem.

Mekhail says the work underscores the importance of cross-disciplinary collaboration.

“The brain power behind every project is crucial. Every team member counts. Also, every right collaborator added to the research project is akin to earning another doctorate in a new specialty – it’s powerful,” he says.

Mekhail notes the discovery is also relevant to premature aging conditions like progeria. The rare genetic condition causes rapid aging within the first two decades of life, commonly leading to early death.

Progeria is linked to a gene coding for lamin A. Mutations in this gene reduce the rigidity of the nuclear envelope. The team found that expression of mutant lamin A is sufficient to induce the tubules, which DNA damaging agents further boosted. The team thinks that even weak pressure on the nuclear envelope spurs the creation of tubules in premature aging cells.

The findings suggest that in progeria, DNA repair may be compromised by the presence of too many or poorly regulated tubules. The study results also have implications for many other clinical conditions, Mekhail says.

“It’s exciting to think about where these findings will lead us next,” says Mekhail. “We have excellent colleagues and incredible trainees here at Temerty Medicine and in our partner hospitals. We’re already working toward following this discovery and using our work to create novel therapeutics.”

The research was supported by the Canadian Institutes of Health Research, Royal Society of Canada, U of T and Princess Margaret Hospital.

U of T 'self-driving lab' to focus on next-gen human tissue models

Christopher.Sorensen — Thu, 26 Oct 2023 15:15:29 +0000

U of T 'self-driving lab' to focus on next-gen human tissue models

Christopher.Sorensen Thu, 10/26/2023 - 11:15

Cutline

The Self-Driving Lab for Human Organ Mimicry will use organoids and organs-on-chips – a well plate is pictured here – to allow researchers to move potential therapeutics to human clinical trials more rapidly (photo by Rick Lu)

Anika Hazra

Topic

Institutional Strategic Initiatives

Acceleration Consortium

Donnelly Centre for Cellular & Biomolecular Research

Artificial Intelligence

Faculty of Applied Science & Engineering

Robotics

Subheadline

The Self-Driving Laboratory for Human Organ Mimicry is one of six self-driving labs launched by the Acceleration Consortium to drive research across a range of fields

The ��Ƶ is home to a new “self-driving lab” that will allow researchers to better understand health and disease – and to more rapidly test the efficacy and toxicity of new drugs and materials.

Based at the Donnelly Centre for Cellular and Biomolecular Research, the Self-Driving Laboratory for Human Organ Mimicry is the latest self-driving lab to spring from a historic $200-million grant from the Canada First Research Excellence Fund to the Acceleration Consortium – a global effort to speed the discovery of materials and molecules that is one of several U of T institutional strategic initiatives.

The new lab will be led by Milica Radisic, Canada Research Chair in Organ-on-a-Chip Engineering and professor of biomedical engineering in the Faculty of Applied Science & Engineering, and Vuk Stambolic, senior scientist at the Princess Margaret Cancer Centre, University Health Network, and a professor of medical biophysics in the Temerty Faculty of Medicine.

“The lab will innovate new complex cellular models of human tissues, such as from the heart, liver, kidney and brain, through stem-cell-derived organoids and organ-on-a-chip technologies,” said Radisic. “In partnership with the Princess Margaret Cancer Centre, the lab will also enable automation of patient-derived tumour organoid cultures to accelerate the discovery of new cancer treatments.”

Tumour organoids stained with fluorescent dyes (image courtesy of Nikolina Radulovich and Laura Tamblyn)

The Self-Driving Laboratory for Human Organ Mimicry is one of six self-driving labs launched by the Acceleration Consortium at U of T to drive research across a range of fields, including materials, drug formulation, drug discovery and sustainable energy.

How does a self-driving lab work? Once set up, it runs with robots and artificial intelligence performing as much as 90 per cent of the work. That, in turn, speeds up the process of discovery by freeing researchers from the tedious process of trial and error so they can focus on higher-level analysis.

“The Self-Driving Lab for Human Organ Mimicry will enable other self-driving labs to develop new materials and drugs by rapidly determining their efficacy, as well as their potential toxic effects and other impacts on human tissues,” said Stambolic. “While animal testing is typically the go-to method to assess the safety of new molecules made for humans, this lab will replace trials involving animals with organoids and organs-on-chips. This will allow us to advance to human clinical trials much more quickly.”

Professors Milica Radisic and Vuk Stambolic (supplied images)

“The goal of our self-driving labs is to use AI to move the discovery process forward at the necessary pace to tackle global issues,” said Alán Aspuru-Guzik, director of the Acceleration Consortium and professor of chemistry and computer science in the Faculty of Arts & Science. “The Human Organ Mimicry SDL, as well as other self-driving labs launched through the Acceleration Consortium, will establish U of T and our extended research community as a global leader in AI for science.”

Donnelly Centre Director Stephane Angers says the centre is an ideal environment for the new lab, citing the the international hub for cross-disciplinary health and medical research’s reputation as a hotspot for technological innovation – one that offers resources to the wider research community.

“The Donnelly Centre is a thriving research community because it was founded on the principle of interdisciplinary collaboration,” said Angers, a professor of biochemistry and pharmaceutical sciences. “Our research strengths in computational biology, functional genomics and stem cell biology will catalyze the development and success of the Self-Driving Lab for Human Organ Mimicry.”

The launch of the new lab will also expand the Donnelly Centre’s team of experts with the hiring of five new staff who will work to make the self-driving lab fully automated. The lab is expected to be operational by the end of the year

“The Donnelly Centre is one of the foremost research institutes in the world, with outstanding strength in genomics, model organisms, organoids, computational biology and many other areas,” said Justin Nodwell, vice-dean of research and health science education at the Temerty Faculty of Medicine.

“I’m delighted to hear about the addition of the Acceleration Consortium’s artificial intelligence-powered self-driving lab to the centre’s existing technical base. It will facilitate new lines of research by some of the best minds in the country.”

Why is COVID-19 more severe in some people? Researchers use genetics, data science to find out

Christopher.Sorensen — Wed, 25 Oct 2023 14:08:53 +0000

Why is COVID-19 more severe in some people? Researchers use genetics, data science to find out

Christopher.Sorensen Wed, 10/25/2023 - 10:08

Cutline

(Photo by Cole Burston/AFP/Getty Images)

Tyler Irving

Topic

Institutional Strategic Initiatives

COVID-19

Data Sciences Institute

Sunnybrook Health Sciences Centre

Sinai Health

Dalla Lana School of Public Health

Unity Health

Computer Science

Faculty of Arts & Science

Hospital for Sick Children

Mount Sinai Hospital

St. Michael's Hospital

Statistical Sciences

Women's College Hospital

Subheadline

With the help of U of T's Data Sciences Institute, researchers from the university and partner hospitals gathered more than 11,000 full genome sequences from across Canada

Why do some people have a more severe course of COVID-19 disease than others? A genome sequence database created by an international collaboration of researchers, including many from the ��Ƶ and partner hospitals, may hold the answers to this question – and many more.

The origins of the Canadian COVID-19 Human Host Genome Sequencing Databank, known as CGEn HostSeq, can be traced to the earliest days of the pandemic.

Lisa Strug, senior scientist at The Hospital for Sick Children (SickKids) and academic director of U of T’s Data Sciences Institute, one of several U of T institutional strategic initiatives, says genetic data was top of mind for her and other researchers in late 2019 and early 2020 as reports of a novel form of coronavirus emerged from China and then other locations across the globe.

Lisa Strug (Photo courtesy The Hospital for Sick Children)

“In my research, I use data science techniques to map the genes responsible for complex traits,” says Strug, who is a professor in U of T’s departments of statistical sciences and computer science in the Faculty of Arts & Science and in the biostatistics division of the Dalla Lana School of Public Health.

“We knew that genes were a factor in the severity of previous SARS infections, so it made sense that COVID-19, which is caused by a closely related virus, would have a genetic component, too.

“Very early on, I started getting messages from several scientists who wanted to set up different studies that would help us find those genes.”

Over the next few months, Strug – who is also the associate director of SickKids’ Centre for Applied Genomics, one of three sites across Canada that form CGEn, Canada’s national platform for genome sequencing infrastructure for research – collaborated with nearly 100 researchers from across U of T and partner hospitals and institutions, as well as other researchers from across Canada to enrol individuals with COVID-19 and sequence their genomes.

Some of the key team members from the Toronto community included:

Stephen Scherer, chief of research at SickKids Research Institute and a University Professor in U of T’s Temerty Faculty of Medicine, as well as director of the U of T McLaughlin Centre
Rayjean Hung, associate director of population health at the Lunenfeld-Tanenbaum Research Institute, Sinai Health, and a professor in U of T’s Dalla Lana School of Public Health
Angela Cheung, clinician-scientist at University Health Network, senior scientist at Toronto General Hospital Research Institute and a professor in U of T’s Temerty Faculty of Medicine
Upton Allen, head of the division of infectious diseases at SickKids and a professor in U of T’s Temerty Faculty of Medicine

The projected was initiated by Scherer and CGEn’s Naveed Aziz, along with Strug, and a $20-million grant was secured from Innovation, Science and Economic Development Canada, administered through Genome Canada.

“We had to go right to the top to get this project funded fast and our labs and teams worked seven days a week on the project right through the pandemic,” Scherer recalls.

Identifying associations between individual genes and complex traits typically requires thousands of genomes – both from those with the trait and those without. Though there was no shortage of cases to choose from, it was critical to gather and sequence DNA – and then organize the data in a way that would be ethical, efficient and useful to researchers now and in the future.

“One of our key mandates at the Data Sciences Institute is developing techniques and programs that ensure that data remains as open, accessible and as re-producible as it can be,” Strug says.

“That vision was brought to bear as we assembled the data infrastructure for this project – for example, ensuring that consent forms were as broad as possible so that this data could be linked with other sources, from electronic medical records to other health databases.

“We wanted to be sure that even after the COVID-19 pandemic was over this could be a national whole genome sequencing resource to ask all kinds of questions about health and our genes. The development of the database and its open nature also enabled Canada to collaborate effectively with similar projects in other countries.”

Partner hospitals and institutions:

The Hospital for Sick Children (SickKids)
Lunenfeld-Tanenbaum Research Institute, Sinai Health
Mount Sinai Hospital, Sinai Health
St Michael’s Hospital, Unity Health Toronto
University Health Network (UHN)
Princess Margaret Cancer Centre, UHN
Ontario Institute for Cancer Research
Women’s College Hospital
Toronto General Hospital, UHN
Baycrest Health Sciences

In the end, the project gathered more than 11,000 full genome sequences from across Canada, representing patients with a wide range of health outcomes. Those data were then combined with even more sequences from patients in other countries under what came to be called the COVID-19 Host Genetics Initiative.

It didn’t take long for patterns to start to emerge. A paper published in Nature in 2021 identified 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19.

Since then, even more data have been added, and subsequent analysis has confirmed the significance of existing loci while also identifying new ones. The most recent update to the project, published in Nature earlier this year, brings the total number of distinct, genome-wide significant loci to 51.

“Identification of these loci can help one predict who might be more prone to a severe course of COVID-19 disease,” says Strug.

“When you identify a trait-associated locus, you can also unravel the mechanism by which this genetic region contributes to COVID-19 disease. This potentially identifies therapeutic targets and approaches that a future drug could be designed around.”

While it will take many more years to fully untangle the effects of the different loci that have been identified, Strug says that the database is already showing its worth in other ways.

“It can be difficult to find datasets with whole genome sequence and approved for linkage with other health information that are this large, and we want people to know that it is open and available for all kinds of research well beyond COVID through a completely independent data access committee,” she says.

“For example, several investigators from across Canada have been approved to use these data and we’ve even provided funding to trainees to encourage them to develop new data science methodologies or ask novel health questions using the CGen HostSeq data.”

“This was a humongous effort, where researchers from across Canada came together during the COVID-19 pandemic to recruit, obtain and sequence DNA from more than 11,000 Canadians in a systematic, co-operative, aligned way to create a made-in-Canada data resource that will hopefully be useful for years to come. I think that was really miraculous.”

Researchers challenge long-standing theory guiding nanoparticle treatment of tumours

Christopher.Sorensen — Mon, 25 Sep 2023 13:25:30 +0000

Researchers challenge long-standing theory guiding nanoparticle treatment of tumours

Christopher.Sorensen Mon, 09/25/2023 - 09:25

Cutline

PhD student Matthew Nguyen and Professor Warren Chan found that about 45 per cent of nanoparticles that accumulate in tumours end up exiting them (supplied photos)

Anika Hazra

Topic

Institute of Biomedical Engineering

Donnelly Centre for Cellular & Biomolecular Research

Faculty of Applied Science & Engineering

University Health Network staff

Subheadline

Study could explain why some cancer treatments are struggling in clinical trials

Researchers at the ��Ƶ have developed a new theory to explain how nanoparticles enter and exit the tumours they are meant to treat, potentially rewriting an understanding of cancer nanomedicine that has guided research for nearly four decades.

The Enhanced Permeability and Retention (EPR) effect, a concept largely unchallenged since the mid-1980s, posits that nanoparticles enter a tumour from the bloodstream through gaps between the endothelial cells that line its blood vessels – and then become trapped in the tumour due to dysfunctional lymphatic vessels.

“The retention aspect of the EPR theory is contingent on the lymphatic vessel cavity being too small for nanoparticles to exit, thereby helping nanoparticles that carry cancer-fighting drugs to stay in the tumours,” said Matthew Nguyen, a PhD student in the Institute of Biomedical Engineering in the Faculty of Applied Science & Engineering and the Donnelly Centre for Cellular and Biomolecular Research,

“But we found around 45 per cent of nanoparticles that accumulate in tumours will end up exiting them.”

Nguyen, who is a member of the lab of Professor Warren Chan, is the lead author on a new study that challenges the long-standing theory that was recently published in the journal Nature Materials. The researchers’ findings help explain why treatments based on the EPR effect are failing in clinical trials, building on earlier research from the Chan lab that showed less than one per cent of nanoparticles actually reach tumours.

Schematic of nanoparticle exit via the intratumoural lymphatic vessels. Nanoparticles in the tumour move towards the lymphatic vessel, cross the vessel wall and drain into the vessel lumen (Nguyen, L.N.M., Lin, Z.P., Sindhwani, S. et al.)

The researchers found that, contrary to the EPR effect, nanoparticles can leave tumours through their lymphatic vessels. The exit method for a nanoparticle depends on its size, with larger ones (50-100 nanometres wide) more likely to leave through lymphatic vessels in the tumours, and smaller ones (up to 15 nanometres wide) more likely to leave through lymphatic vessels surrounding the tumours.

In rare cases, nanoparticles will exit through blood vessels.

Nanoparticle exit from tumours occurs through spaces in the lymphatic vessel walls and transport vesicles that carry them across these walls. The researchers showed that nanoparticles will re-enter the bloodstream following lymphatic drainage, and hypothesized that these nanoparticles will eventually return to the tumour for another opportunity to treat it.

Disproving the EPR effect was no easy feat. The Chan lab spent six years working to understand why nanoparticles do not accumulate in tumours effectively. Prior to this study, the lab focused on how nanoparticles enter tumours in the first place. Through this and other studies, the lab developed a competing theory to the EPR effect, called the Active Transport and Retention (ATR) principle.

Nguyen noted that the field of nanomedicine has evolved since the publication of the nanoparticle entry study in 2020. “We got more pushback from other researchers on that study compared to this one,” he said. “People have started to accept that the EPR effect is flawed.”

With nearly half of accumulated nanoparticles exiting tumours, mostly through lymphatic vessels, future research could address this issue through nanoparticle treatments that prevent lymphatic drainage.

“We are excited to have a better understanding of the nanoparticle tumour delivery process,” said Chan. “The results of these fundamental studies on nanoparticle entry and exit will be important for engineering nanoparticles to treat cancer.”

The study’s findings, if applied across the field of cancer nanomedicine, promise a new direction to improve our understanding of how nanoparticles can be used to treat tumours.

“Trying to translate cancer nanomedicine to the clinic is like a working with a black box – some drugs work, some don’t, and it’s difficult to know why,” said Gang Zheng, associate research director at the Princess Margaret Cancer Centre and a professor of medical biophysics in U of T’s Temerty Faculty of Medicine who was not involved in the study.

“Chan’s dedication to better understanding the mechanisms of nanoparticle uptake and exit is shining light on these processes to help make our translation efforts more efficient and successful.”

The research was supported by the Canadian Cancer Society, the Canadian Institutes of Health Research, NanoMedicines Innovation Network and the Canada Research Chairs program.

Gelareh Zadeh, a neurosurgeon-scientist, recognized with Canada Gairdner Momentum Award

Christopher.Sorensen — Thu, 30 Mar 2023 15:50:07 +0000

Gelareh Zadeh, a neurosurgeon-scientist, recognized with Canada Gairdner Momentum Award

Christopher.Sorensen Thu, 03/30/2023 - 11:50

Cutline

Gelareh Zadeh, a researcher at University Health Network and U of T, is one of two winners of the inaugural Gairdner Momentum Award for her work on the classification and treatment of brain tumours (photo courtesy of UHN StRIDe)

Topic

Gelareh Zadeh, a researcher at University Health Network and the ��Ƶ, has been recognized with a 2023 Canada Gairdner Award for her work on the classification and treatment of brain tumours.

She is one of two winners of the inaugural Momentum Award, created by the Gairdner Foundation to recognize mid-career researchers who have made significant discoveries with the potential to improve human health.

“It is such an honour to receive this award from the Gairdner Foundation,” said Zadeh, a senior scientist at University Health Network and a professor of surgery in U of T’s Temerty Faculty of Medicine.

“I attribute my success in large part to the highly skilled and integrated research and clinical teams that I work with at University Health Network. My team’s achievements in translational brain research simply would not be possible without the exceptional researchers, trainees, neuro-oncologists, surgical teams and patients that we work with every day.”

The Gairdners are Canada’s most prestigious honour for health-related research and have developed a reputation since their inception in 1957 as a precursor to the Nobel Prize, with roughly a quarter of Gairdner recipients later winning a Nobel.

Zadeh was recognized for her contributions to the understanding of brain tumours. Her work has led to a new molecular classification of meningiomas, one of the most common types of brain tumours – an advance that could produce more effective treatments, models for predicting patient outcomes and biomarkers of treatment response.

Her research integrates molecular, genomic and epigenomic techniques with experimental models of brain tumours to accelerate translational research.

Zadeh has also led international efforts to define the genomic landscape of neuronal tumours that have not been the focus of significant biological research, including schwannomas, peripheral nerve tumours and malignant peripheral nerve sheath tumours. These efforts have revealed novel fusion proteins and resulted in the molecular sub-classification of schwannomas.

Additionally, her team has identified two biological pathways that drive the progression of benign peripheral nerve tumours toward malignant sarcomas. These molecular pathways provide a better biological understanding of tumour transformation, but also offer targets that could be used to develop therapeutic strategies, including the repurposing of existing pharmaceuticals.

In collaboration with researchers at the Princess Margaret Cancer Centre, Zadeh has advanced the development of blood-based biomarkers that can help discriminate among different brain tumour types and potentially to track response to therapy and early recurrence of disease.

Zadeh holds the Dan Family Chair in the division of neurosurgery in U of T’s department of surgery and is the first woman in Canada to be named neurosurgery chair. She is also the head of neurosurgery at Toronto Western Hospital and co-director of the Krembil Brain Institute. She leads a 30-member research team at Princess Margaret Cancer Centre.

Her other prestigious honours include the William E. Rawls Prize from the Canadian Cancer Society, the Top 25 Women of Influence Award, and the Ab Guha Award, which is jointly awarded by the Society of Neuro-Oncology and American Association of Neurological Surgeons.

The Gairdner Momentum Award comes with a $50,000 prize and will be presented during Gairdner Science Week in October 2023.

A version of this story originally appeared at University Health Network.

U of T mourns the death of Queen Elizabeth II, lowers flags to half-mast

Christopher.Sorensen — Thu, 08 Sep 2022 23:35:48 +0000

U of T mourns the death of Queen Elizabeth II, lowers flags to half-mast

Christopher.Sorensen Thu, 09/08/2022 - 19:35

Cutline

Her Majesty Queen Elizabeth II, who died at the age of 96, was the longest-serving monarch in British history (photo by Tim Graham/Getty Images)

Rahul Kalvapalle

Topic

Global Lens

Faculty of Arts & Science

Sinai Health

Massey College

Meric Gertler

Mount Sinai Hospital

Munk School of Global Affairs & Public Policy

Queen

Royalty

St. George

Thomas Fisher Rare Book Library

U of T Libraries

U of T Mississauga

U of T Scarborough

The ��Ƶ is mourning the death of Her Majesty Queen Elizabeth II, the longest-serving monarch in British history, who visited the university on numerous occasions.

Flags on all three U of T campuses are being lowered to half-mast in memory of the Queen, who died Thursday at Balmoral Castle in Scotland at the age of 96. They will remain at half-mast until the day of her state funeral.

The university will also mark the event by having carillonists play the bells in Soldiers’ Tower on Friday at noon, tolling the largest bell once for each year of the Queen’s age at the time of her passing. The royal anthem and O Canada will also be played.

U of T President Meric Gertler said the U of T community joins all Canadians in mourning the loss of the sovereign, noting that, before acceding to the throne, she promised to devote her life to the service of her people.

“She fulfilled that promise with unparalleled grace and dignity, and in so doing set a magnificent example for us all,” President Gertler said in a statement. “Her unfailing devotion to duty has been a constant source of strength and continuity for generations of Canadians as well as countless others around the world.

“Indeed, it is difficult to imagine a world without her.”

Flags fly at half mast at, from left to right, U of T Mississauga, St. George and U of T Scarborough to mark the Queen’s death on Sept. 8, 2022 (photos by Nick Iwanyshyn, Johnny Guatto and Raquel Russell)

He also highlighted the Queen’s contributions to international peace and solidarity through the Commonwealth and noted the U of T community has been enriched by the contributions of students, faculty, librarians, staff and alumni who arrived from or live in fellow Commonwealth countries.

“In tribute to Her Majesty, in this time of sadness and in the years to come, let us remember and learn from her life of dedicated and extraordinarily generous service to others, and give thanks for a life very well lived.”

Princess Elizabeth and the Duke of Edinburgh are greeted at Hart House by U of T Chancellor Vincent Massey (Walter F. Mackenzie/��Ƶ Archives)

The Queen’s passing comes 14 months after her husband Prince Philip, the Duke of Edinburgh, died aged 99.

Princess Elizabeth visits Hart House with U of T Chancellor Vincent Massey on Oct.13, 1951 (Walter F. Mackenzie/��Ƶ Archives)

Prime Minister Justin Trudeau said that it is with the “heaviest of hearts” that Canadians learned of the passing of the country’s longest-reigning sovereign.

“For most Canadians, we have known no other Sovereign. Queen Elizabeth II was a constant presence in our lives. Time and again, Her Majesty marked Canada’s modern history,” he said in a statement.

Born Elizabeth Alexandra Mary on April 21, 1926, Queen Elizabeth II ascended to the crown in 1952 at age 25. She went on to become the longest-reigning monarch in British history, marking her Platinum Jubilee this past February.

She is to be succeeded as monarch by her eldest son Charles, Prince of Wales – now King Charles III.

David Onley, former lieutenant governor of Ontario and a senior lecturer in the department of political science at U of T Scarborough, said he has warm recollections of meeting the Queen at Buckingham Palace in 2008.

“The experience my wife and I had was quite amazing to us in that the conversation was not superficial. The Queen really engaged in our conversation,” Onley said.

He added that the Queen took great interest in the results of Canada’s federal election, which had taken place the night before. “I was really quite amazed as to how well-briefed she was. She wanted to know about Stephen Harper, she wanted to know about why the Liberals had lost so badly on that occasion – so it wasn’t just a superficial chit-chat.

“At the same time, I would say that she interacted with everybody like that – and that was one of the fundamental reasons for her passing being felt by so many people. Because everybody has stories – if you met the Queen, you had a story – and that was because of her degree of engagement.”

Onley said the Queen’s impeccable reputation during her seven-decade reign – he noted that her first prime minister was Winston Churchill and her last, the recently elected Elizabeth Truss; and that she had met all but one of the U.S. presidents since the Second World War – was testament to her complete devotion to the role.

“This is a particular accomplishment, and you would not have that kind of reputation if you were just effectively mailing in the responsibilities,” Onley said. “She saw it as a lifetime of service and executed that service right to the very end.”

He added that the frequency and range of the Queen’s visits to Ontario and Canada “give you the sense of the degree of interest that she had in this province, and other provinces as well.”

Queen Elizabeth II attends the Festival of Ontario at the CNE in 2002, making a stop in front of the U of T Blue Sky Solar Racing Team’s display (photo via Flickr)

Queen Elizabeth II and the Duke of Edinburgh visited Toronto seven times, with their first visit taking place in 1951, four months before the Queen’s coronation. On that occasion, the royal couple were driven to the steps of Hart House, where they waved to cheering crowds and posed for photos.

In 1973, the Queen returned to Toronto and laid the cornerstone for the new Mount Sinai Hospital, part of Sinai Health and one of U of T’s partner hospitals. The hospital is located next to Princess Margaret Cancer Centre, named in honour of the Queen’s sister.

In 2002, the royal couple visited Toronto again during the Queen’s Golden Jubilee, which coincided with U of T’s 175^th anniversary. During the celebrations, the Queen visited a U of T display where she spoke with undergraduate students from the Blue Sky Solar Racing team who were present with their solar-powered car.

“I recall that the Queen had such a presence,” said Nicolle Wahl, director of content in U of T Mississauga’s Office of Communications, who was present at the U of T display. “[She was] very warm and curious – and it was wonderful to see how excited the students were to meet her.”

A letter written by Princess Elizabeth to U of T Chancellor Vincent Massey dated Feb. 17, 1952 (photo by Larysa Woloszansky)

The Queen’s 22^ndand final tour of Canada took place in 2010 and included a visit to Queen’s Park – named in honour of her great-great-grandmother Queen Victoria and located amid U of T’s St. George campus – where she presented Ontario Medals for Good Citizenship and waved to thousands of cheering well-wishers.

The Queen’s impact on U of T did not end with her last visit to Toronto, however. In 2017, Massey College announced that the Queen agreed to designate the college’s St. Catherine’s Chapel as the third Chapel Royal in Canada, which made it the first interdenominational Chapel Royal in the country.The request for the designation was made by John Fraser, then the master of Massey College, with the support of the Mississaugas of the New Credit First Nation. It was inspired in part by the Truth and Reconciliation Commission of Canada’s Calls to Action.

U of T’s Thomas Fisher Rare Book Library has one of 25 souvenir Bibles created to mark the Queen’s coronation in 1953 (photo by Johnny Guatto)

The Queen’s ties with Massey College can be traced back to her close relationship with the college’s founder Vincent Massey, who was Canada’s 18^th Governor General and a U of T chancellor from 1947 to 1953.

Letters written by the Queen to Massey – and preserved at U of T’s Thomas Fisher Rare Book Library – speak to a warm personal rapport.

In one letter dated February 1952, the Queen responded to a letter of condolence sent to her by Massey upon the passing of her father, King George VI. In her letter, the Queen expresses her gratitude for Massey’s condolences and notes that her father was in much better condition when Massey had last met him, but had then taken a turn for the worse. The Queen also states her regret at the fact that she was on a tour in Africa when her father died and was saddened by not being able to be home to comfort and console her mother and sister.

Another letter written from Balmoral Castle – where the Queen would eventually take her last breath – thanked Massey for being a great governor general. In another letter to Massey, written from Buckingham Palace in 1957, the Queen recounts her visit to the United States.

A letter written by Queen Elizabeth II to Vincent Massey on the occasion of his retirement as governor general of Canada (photo by Johnny Guatto)

The Thomas Fisher Rare Book Library is also in possession of one of 25 souvenir Bibles created to mark the Queen’s coronation in 1953. Bible #1 was used for the coronation ceremony – the Queen gifted Bible #17 to Massey.

Randall Hansen, professor in the department of political science in the Faculty of Arts & Science and the director of the global migration lab at the Munk School of Global Affairs & Public Policy, said the Queen’s many accomplishments include overseeing a modernization of the monarchy – noting as examples her decision to agree to pay income tax and the landmark wedding of Prince Harry and Meghan Markle.

“Leaving aside how it all ended, the marriage of Meghan Markle and Prince Harry was a moment of a highly modern monarchy – an inter-racial marriage and a Black Baptist American minister who oversaw the service.”

He added that the Queen’s son and heir to the throne will benefit from the prestige of the monarchy and the Queen’s impact on the institution.

“It is the institution of the Crown, it is the institution of the monarchy that bestows the prestige … that institution will bequeath on him the full prestige of the monarchy,” Hansen said. “I suspect that he’s going to be quite a successful King.”

Hansen said it was remarkable that Queen Elizabeth II, over the course of an extraordinarily long reign, was not embroiled in a scandal of any significance.

“The Queen somehow managed to be above all of that, decade after decade after decade.”

John Dick and Zulfiqar Bhutta win Canada Gairdner Awards

Christopher.Sorensen — Tue, 05 Apr 2022 13:20:56 +0000

John Dick and Zulfiqar Bhutta win Canada Gairdner Awards

Christopher.Sorensen Tue, 04/05/2022 - 09:20

Cutline

John Dick and Zulfiqar Bhutta have been honoured with 2022 Canada Gairdner Awards, the country’s most prestigious awards for medical and health science (photos courtesy of Images by Delmar and The Hospital for Sick Children)

Jim Oldfield

Topic

Dalla Lana School of Public Health

Pediatrics

Gairdner Award

Hospital for Sick Children

Molecular Genetics

Nutritional Sciences

Two researchers at the ��Ƶ and its hospital partners – one a stem cell biologist, the other a global health researcher – have been honoured with 2022 Canada Gairdner Awards, the country’s most prestigious awards for medical and health science.

John Dick was recognized with a Gairdner International Award for the discovery of leukemic stem cells and later work on the diagnosis and treatment of acute myeloid leukemia. He first received the news from Janet Rossant, president and scientific director of the Gairdner Foundation, earlier this year.

“When Janet called, it was definitely an ‘Oh my gosh’ moment,” said Dick, a professor of molecular genetics at U of T’s Temerty Faculty of Medicine and a senior scientist at Princess Margaret Cancer Centre, University Health Network.

“I recall being asked to sit on an evaluation panel for the Gairdners in the early 1990s, not long after setting up my lab in Toronto. That seemed like the epitome of achievement and I never imagined in my wildest dreams that one day I’d receive a Gairdner award.”

The John Dirks Canada Gairdner Global Health Award went to Zulfiqar Bhutta for his research on community-based and policy interventions in child and maternal health, especially among vulnerable populations.

“I’m very pleased and grateful,” said Bhutta, a professor in the departments of nutritional sciences and pediatrics at Temerty Medicine and at the Dalla Lana School of Public Health, and the director of the Centre for Global Child Health and a senior scientist at The Hospital for Sick Children.

“There are not many awards for research in global or public health, and the Gairdners occupy a special place in Canada and globally,” said Bhutta, who moved to Toronto in 2013 and maintains a research group at the Aga Khan University in Pakistan. “It really is a pinnacle and most humbling.”

John Dick: Growing Toronto’s stem cell legacy

Dick and his lab were the first to discover and describe leukemia stem cells, which can self-renew and drive both cancer growth and relapse after treatment.

Those findings have led to new clinical approaches for acute myeloid leukemia and related blood cancers, and spurred research on the role of stem cells in solid tumours of the colon, breast and brain, among other sites.

Dick said he didn’t set out to discover leukemia stem cells, but instead began by “plugging away” at basic science on the blood system in mice, experimenting with ways to put genes into stem cells.

In a key advance in the late 1980s, Dick’s lab developed a way to transplant human blood stem cells into immune-deficient mice. This “xenograft assay” was a world-first and enabled Dick and other researchers to track and test the human cells’ growth and replication, albeit in the living system of the mouse.

At the same time, Dick’s lab created the first xenograft models of human leukemia and developed a method to purify leukemia stem cells, allowing for detailed comparisons of those cells and leukemia cells without stem-like properties.

“Most people thought those early experiments wouldn’t work,” said Dick. “But lo and behold some of them worked beautifully, and we were able to characterize leukemia stem cells and non-stem cells. Leukemia is a caricature of normal development and we exploited that.”

Dick and his team began counting individual cells – much like James Till and Ernest McCulloch after their discovery of stem cells in Toronto in 1961, Dick noted. They made the startling finding that stem cells are extremely rare in acute myeloid leukemia – roughly one in a million, in a given population of leukemia cells.

They later found that relapse of acute myeloid leukemia is linked to the survival of leukemia stem cells after therapy and, using patient blood samples, they showed that leukemia stem cells that cause relapse are already present in the blood the day the patient first shows up at the clinic and before therapy begins.

Dick’s lab eventually developed a 17-gene “stemness score” that physicians use to predict patient risk and outcomes, which increasingly helps guide therapeutics. “It’s a new kind of approach for effective patient-specific intervention, which is gratifying,” Dick said.

Dick credits many colleagues for his successes, starting with the trainees in his lab. He said their technical skills and passion were critical, and that their ideas were often essential.

“For most of our findings, no one had the right ideas,” Dick said. “We just threw our thoughts in a melting pot – the good and the bad, and the resulting fusion took us in completely unexpected directions. In that intellectual foment, trainees have contributed so much. They’ve been the best post-docs and graduate students you could imagine.”

He also thanked his clinical collaborators at Princess Margaret Cancer Centre and other hospitals, as well as his colleagues at U of T.

“Human disease is the best sourcebook for raising and testing research questions, so I needed that constant interchange with clinicians,” Dick said. “But I benefited hugely from the intellectual rigour and collegiality of my colleagues in molecular genetics. I don’t think I could have done this work anywhere but Toronto.”

Zulfiqar Bhutta: Thinking big for the smallest and vulnerable

Bhutta’s career began in neonatology in Pakistan, but he soon expanded his focus beyond infants.

“I realized you can’t work with babies without working with mothers – and the moment you start working with mothers, you get to social determinants of health,” said Bhutta, the first U of T faculty member to win the John Dirks Canada Gairdner Global Health Award.

For more than three decades, Bhutta’s research has influenced policy and practice in global child and maternal health through implementation science, research synthesis and trials, as well as studies of malnutrition and obesity, among other approaches.

“I’ve learned as I went along, but I’ve been fortunate to work in a variety of areas, often on large-scale projects, with opportunities to make a difference in the short- and long-term,” said Bhutta, who is also affiliated with U of T’s Joannah & Brian Lawson Centre for Child Nutrition.

Bhutta and his colleagues at Aga Khan University provided some of the first scientific evidence on the impact of “lady health workers” in community-based interventions in Pakistan. The government of Benazir Bhutto began employing the workers in the mid-1990s, with the goal of reducing child and maternal risk factors and deaths.

Bhutta and his team helped evaluate those interventions in a series of cluster randomized trials – a method common in public health that allows researchers to compare program impacts across groups or clusters of people. Among their findings: using chlorhexidine for cord care during home births reduced neonatal infection and death – and public-sector community health workers working in rural populations could indeed help reduce perinatal fatalities.

They also showed that when women began to visit health facilities, facility-based births increased. Moreover, they found that women’s embrace of the community health system did not falter after the formal period of the intervention ended.

“That’s diffusion of innovation, when improvements become ingrained,” said Bhutta. “People said that women would suffer de-development after the initial intervention, but that did not happen. The lesson was that when you increase capacity around women’s health, you can move away and they never look back.”

Bhutta and his team provided evidence for expansion of the community-based worker model in Pakistan and countries in the Global South, but their work also highlighted the limits of what those workers can achieve.

“You can’t do much about a woman who is bleeding to death without access to a facility with a blood bank,” Bhutta said. “I’ve seen many efforts to upgrade community interventions to physician-level care fall flat because community workers are not physicians.”

Many of those failures were closely linked to social determinants of health, Bhutta said. He recalled that in a Pakistani hospital where his wife worked in the 1990s, pregnant women kept arriving dead at the hospital despite living just a few kilometres away. It turned out the delays were often due to an imbalance in decision-making power between males in females, a lack of money for transport or misunderstanding of the severity of the medical crisis.

“These problems don’t have a biomedical solution,” said Bhutta. “They need education, women’s empowerment, and building social and economic resources at the community level.”

Today, Bhutta continues to pursue research on child and maternal health in the Global South and among marginalized populations in high-income countries. But he is broadening his focus further to address another social determinant of health: climate change.

“I would like to work on solutions to climate change for the poorest of poor before countries agree and develop policy,” said Bhutta. “People are dying now from food shortages and heat shocks. I want to help bring communities together on a self-help basis to promote innovations without the need for external supports. Watch that space.”

The Gairdner Foundation was established in 1957 to recognize research that impacts human health and has since given 402 awards to scientists around the world. About a quarter of those researchers later received Nobel Prizes. The foundation gives seven awards annually. Each recipient receives $100,000 and participates in public lectures, research symposia and other outreach events. The foundation is supported by the Government of Canada.

Gut bacteria linked to immune suppression in pancreatic cancer: Study

Christopher.Sorensen — Wed, 09 Feb 2022 17:20:25 +0000

Gut bacteria linked to immune suppression in pancreatic cancer: Study

Christopher.Sorensen Wed, 02/09/2022 - 12:20

Cutline

Tracy McGaha, a senior scientist at Princess Margaret Cancer Centre and a U of T professor of immunology, says that "in some conditions, the constituency of the microbiome may have a negative impact" on cancer outcomes (photo courtesy of Tracy McGaha)

Jim Oldfield

Topic

Immunology

Research and Innovation