Temerty Faculty of Medicine

Institute of Biomedical Engineering

Princess Margaret Cancer Centre

Donnelly Centre for Cellular & Biomolecular Research

Faculty of Applied Science & Engineering

University Health Network

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 ��ɫֱ�� 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 ��ɫֱ��’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 ��ɫֱ��’s Temerity 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.”

Caution needed when drawing links between improving symptoms and unproven remedies: Study

Christopher.Sorensen — Fri, 06 Sep 2024 16:03:17 +0000

Caution needed when drawing links between improving symptoms and unproven remedies: Study

Christopher.Sorensen Fri, 09/06/2024 - 12:03

Cutline

(photo by Oleksandra Yagello/Getty Images)

Sunnybrook Staff

Topic

Sunnybrook Health Sciences Centre

Institute of Health Policy Management and Evaluation

Dalla Lana School of Public Health

Subheadline

"Post-hoc bias can play tricks on patients that can eventually lead to serious disappointments – and for health-care workers, it can ultimately lead to shortfalls in care"

People tend to continue with unproven treatments even if there’s no evidence to suggest an initial marginal improvement in symptoms is anything more than a potential coincidence, a new study has found.

"I've noticed many of my patients take unnecessary vitamins, pills or alternative remedies with little evidence to inform their choice, leading to a lot of distraction, wishful thinking and wasted money,” says senior study author Donald Redelmeier, a staff internist and senior scientist at Sunnybrook Health Sciences Centre, and professor in the department of medicine in the ��ɫֱ��’s Temerty Faculty of Medicine.

“Perhaps even more concerning is a false belief that leads to a missed diagnosis that later becomes incurable.”

The study, published in the journal JAMA Network Open, explores “post-hoc bias” – a tendency in reasoning that causes many patients to continue taking dubious or unreliable treatments. The bias encourages a popular misconception: that because one action preceded another later event, the first must have caused the second since it occurred in sequence.

But medical science, the researchers note, stresses that the order of two events does not prove a cause-and-effect since coincidences are frequent. The implication for medical care is that a patient who improved after a treatment is not necessarily a patient who improved because of the treatment.

Instead, other potential explanations include withdrawal from an adverse activity, added rest or the body’s own healing powers.

To test bias across a variety of clinical cases, the researchers ran multiple experiments using hypothetical clinical scenarios administered by a randomized survey of pharmacists and members of the community.

The scenarios described a patient with fatigue or another vague symptom who feels a bit better after trying a vitamin, shampoo, sugar pill or other treatment.

“We found that most respondents suggested continuing the treatment indefinitely even though the change in symptoms might be pure random chance," says Redelmeier, who is also affiliated ICES and the Institute for Health Policy, Management and Evaluation in ��ɫֱ��’s Dalla Lana School of Public Health.

"The post-hoc bias can play tricks on patients that can eventually lead to serious disappointments – and for health-care workers, it can ultimately lead to shortfalls in care."

While attributing an initial improvement in – or lack of – symptoms to a treatment is a quick and intuitive approach, the researchers say the study reinforces the need for both patients and clinicians to be cautious when drawing conclusions.

“An awareness of post-hoc bias will not make it disappear, however we suggest patients and clinicians need to think twice and stay mindful of alternative explanations.”

The study was supported by the Alfred P. Sloan Foundation, a Canada Research Chair in Medical Decision Sciences, Canadian Institutes of Health Research, the PSI Foundation of Ontario and the National Science Foundation.

This story was originally posted at Sunnybrook Research Institute

Researchers propose biologically based classification system for Parkinson’s disease

rahul.kalvapalle — Tue, 20 Aug 2024 16:17:45 +0000

Researchers propose biologically based classification system for Parkinson’s disease

rahul.kalvapalle Tue, 08/20/2024 - 12:17

Cutline

The "SynNeurGe" classification system for Parkinson's disease, proposed by researchers led by Professor Anthony Lang of the University Health Network and ��ɫֱ��, is based on three key biomarkers (photo by FG Trade/Getty Images)

Eileen Hoftyzer

Topic

Department of Medicine

Tanz Centre for Research in Neurodegenerative Diseases

Parkinson's

University Health Network

Subheadline

The classification system could enable advancements in the development of tailored treatments for Parkinson's disease

A team of researchers led by Anthony Lang of the University Health Network and the ��ɫֱ�� have proposed a novel classification system for Parkinson’s disease that considers biological features and not just clinical symptoms.

The "SynNeurGe" system, described by Lang and collaborators in a paper published in The Lancet Neurology, classifies Parkinson’s disease based on three biomarkers: presence or absence of misfolded alpha synuclein protein, which is believed to cause or contribute to the underlying neurodegeneration; evidence of neurodegeneration using imaging techniques; and presence of gene variants that increase disease risk.

The researchers argue that such a classification system is necessary to advance the development of tailored treatments for Parkinson’s disease.

Professor Anthony Lang (supplied image)

“This is a complex group of disorders that may cause similar symptoms, but biologically they're very different,” says Lang, a senior scientist and Lily Safra Chair in Movement Disorders at UHN and a professor in the department of medicine and the Tanz Centre for Research in Neurodegenerative Disease at ��ɫֱ��’s Temerty Faculty of Medicine, where he holds the Jack Clark Chair for Parkinson’s Disease Research

“If we cannot find ways to subdivide patients biologically, then applying a therapy designed to affect one biological pathway may not be effective in another group of patients that doesn't have that same pathway involved – and we won’t really have precision or personalized medicine for Parkinson’s disease.”

Currently, Parkinson’s disease is classified based on clinical presentation and symptoms, but the disease can affect the brain for years, possibly even decades, before symptoms appear. For future therapies to treat the underlying disease rather than just the symptoms, patients will need early intervention and treatments tailored to the biological features of the disease, researchers say.

Similar approaches are being used for other diseases – cancer treatments vary not only by the location of tumors but also their molecular features, and the development of drugs for Alzheimer’s disease is increasingly guided by the specific biological mechanisms involved in the disease.

The SynNeurGe classification system, while based on the three key biomarkers, also considers whether clinical features are present. The different combinations of biomarkers classify the disease into various sub-types.

Lang and co-authors note that such a classification should only be used for research at present, although it will almost certainly have clinical applications.

“Eventually we will see a biological approach influencing clinical care, particularly when we finally have effective disease-modifying therapies,” says Lang. “We currently don’t know how important these biomarkers actually are.

"We need large-scale prospective studies of biomarkers, imaging and clinical features to interpret the results, give patients accurate information about their diagnosis and provide appropriate treatment.”

Lang’s team plans to start conducting such studies of cerebrospinal fluid, skin and blood to look for biomarkers of different sub-types of Parkinson’s disease that will help inform the classification system and the development of tailored therapies.

“Now is the time to think about these diseases not solely based on their clinical manifestations, but to look at the biology and try to separate different biological subtypes so we can ultimately improve treatment for this disease,” Lang says.

Professor Graham Collingridge, director of the Tanz Centre, says Lang and his team’s “landmark paper” is poised to have a significant impact on clinical practice around Parkinson's. “I am delighted that our researchers have played such a key role in this important biological classification,” Collingridge says.

Lang says research by Tanz Centre scholars has contributed significantly to the body of knowledge used to develop the proposed biological classification.

For example, Professor Ekaterina Rogaeva’s research on the genetics and epigenetics of Parkinson’s disease has shown that multiple genes and environments can influence Parkinson’s risk, highlighting the need to tailor therapies based on a patient’s genetic makeup.

Other researchers – including Anurag Tandon, Joel Watts, Martin Ingelsson and Gabor Kovacs – have been studying the role of misfolded alpha synuclein in neurodegeneration as well as cases of Parkinson’s disease where alpha synuclein is absent – which informed how Lang’s team included the protein in the classification.

��ɫֱ�� startup Honeybee acquired by global clinical trials firm Leapcure

rahul.kalvapalle — Fri, 16 Aug 2024 14:55:48 +0000

��ɫֱ�� startup Honeybee acquired by global clinical trials firm Leapcure

rahul.kalvapalle Fri, 08/16/2024 - 10:55

Cutline

(photo courtesy of Leapcure)

Rahul Kalvapalle

Topic

Our Community

Faculty of Applied Science & Engineering

��ɫֱ�� Entrepreneurship

Health Innovation Hub

Impact Centre

Innovation & Entrepreneurship

ONRamp

Startups

Subheadline

Co-founded by Catherine Chan and Weiwei Li, Honeybee Trials' platform helps clinical trial recruiters find, screen and manage patients for their research

Honeybee Trials, a ��ɫֱ�� startup that connects research teams with patients and study participants, has been acquired by global clinical trials company Leapcure in a deal that is poised to drive more inclusive and affordable trials that’s ultimately applicable to a broader population.

Co-founded by ��ɫֱ�� alumni Catherine Chan and Weiwei Li, Honeybee built a web and mobile platform to help clinical trial teams attract, screen, recruit and manage study participants. Since its founding in 2019, the startup has connected over 30,000 patients and participants to more than 1,000 clinical trials across North America.

Leapcure, headquartered in California, offers an array of solutions that combines people-backed services with data-driven technologies to fill clinical trials for global sponsors and CROs, but can now expand affordable patient recruitment to institutional sites, private sites and biotech firms. Moreover, their work alongside patients and advocacy groups has significantly helped to reach underrepresented communities – a focus that will receive a boost following the purchase of Honeybee.

Chan, who earned a master’s degree in the Temerty Faculty of Medicine’s department of nutritional sciences, says the deal grew out of a desire to partner strategically with a larger company that could provide access to broader sectors within the clinical research world.

Catherine Chan (L) and Weiwei Li (supplied image)

“At Honeybee, we offered competitive pricing for academic and hospital sites, local CROs [contract research organizations] and biotech firms,” Chan says. “With this partnership, we’re able to provide services across all of the different types of trial scopes and sizes.”

She adds that both Honeybee and Leapcure have placed a strong focus on diversity, equity, inclusion and accessibility by helping researchers attract study participants of different ethnicities, ages, genders and sexual orientations – helping make clinical trials more equitable and reflective of the wider population.

“It’s important to us that there's a mission and vision alignment between the companies... it couldn’t be a better fit,” Chan said.

The asset purchase deal for an undisclosed amount, which was announced in an Aug. 13 press release, will see Chan transition from CEO of Honeybee to senior director of product at Leapcure.

“We’re excited to join forces with Catherine and Honeybee. They’ve been really focused on the newest recruitment technologies that are most impactful for both patients and research,” said Leapcure CEO Zachary Gobst. “A big reason that things came together was our alignment on impact first. It’s a credit to how they’ve been approaching their business the right way from the beginning."

Honeybee evolved out of the frustrations that Chan faced in recruiting study participants for her master’s thesis. Motivated to explore solutions, Chan created a prototype that would help match participants with trials; she then enrolled in a one-week accelerator program in the Impact Centre (now the Centre for Entrepreneurship) in the Faculty of Arts & Science.

She soon teamed up with Li, who earned his bachelor’s and master’s of applied science degrees from the Faculty of Applied Science & Engineering, to co-found Honeybee. The startup later joined the Health Innovation Hub (H2i) accelerator and operated out of office space in ��ɫֱ�� Entrepreneurship’s ONRamp facility prior to the COVID-19 pandemic.

With COVID-19 measures encouraging the adoption of digital tools by clinical research teams, Honeybee found itself well-placed to play an important role. “The pandemic provided an opportunity for many tech companies to scale as the market became more open-minded and ready to adopt technologies to help connect them day-to-day," Chan says. "We saw a rapid adoption of Honeybee’s technology during this time where people moved away from traditional recruitment and patient communications to the current age.

“Although digital adoption across other industries has grown quite rapidly, healthcare has lagged behind, rightfully so and for many reasons, but we’re glad the transformation is happening. Just five years ago, clinical trial coordinators were still using paper handouts to recruit on the street and paper calendars to schedule patients.

“The pandemic expedited researchers being able to meet people where they are.”

Chan says the acquisition by Leapcure will enable the rollout of tiered services ranging from low-cost, self-serve tiers – targeting research teams with more modest budgets – to higher levels of service that include dedicated management.

“I’m really excited about the solutions we now have to offer together as well as the next steps in how we’re going to disrupt clinical trials.”

Professor Paul Santerre, co-founder and director of H2i, hailed Chan as "a model outcome" of the accelerator's mission to empower innovators in translating their ideas into products and companies that tackle important problems.

“Catherine and her team’s achievements are transformative in terms of democratizing the recruitment of patients for clinical study cohorts," said Santerre, the Baxter Chair for Health Technology and Commercialization at the University Health Network and professor in the Faculty of Dentistry and Institute of Biomedical Engineering who is cross-appointed to the department of chemical engineering and applied chemistry.

"She has much to still teach us about the power of digital tools and their ethical use to achieve impact in clinical research trials – and this acquisition will accelerate that outcome."

��ɫֱ�� researchers develop AI model to predict 'very dynamic' peptide structures

Christopher.Sorensen — Thu, 15 Aug 2024 12:54:41 +0000

��ɫֱ�� researchers develop AI model to predict 'very dynamic' peptide structures

Christopher.Sorensen Thu, 08/15/2024 - 08:54

Cutline

PhD Graduate Osama Abdin and Professor Philip M. Kim developed a deep-learning model that can predict all possible shapes of peptides, which are are of keen interest to researchers who are developing therapeutics (supplied image)

Anika Hazra

Topic

Donnelly Centre for Cellular & Biomolecular Research

Alumni

Artificial Intelligence

Computer Science

Subheadline

The new model expands on the capabilities of Google DeepMind's AlphaFold, the leading AI system for predicting protein structures

Researchers at the ��ɫֱ�� have developed a deep-learning model that can predict all possible shapes of peptides – chains of amino acids that are shorter than proteins, but perform similar biological functions.

Called PepFlow, the model combines machine learning and physics to model the range of folding patterns that a peptide can assume based on its energy landscape.

Peptides, unlike proteins, are dynamic molecules that can take on a range of conformations. They are involved in many biological processes that are of keen interest to researchers who are developing therapeutics.

“We haven’t been able to model the full range of conformations for peptides until now,” said Osama Abdin, first author on the study and recent PhD graduate of molecular genetics at ��ɫֱ��’s Donnelly Centre for Cellular and Biomolecular Research. “PepFlow leverages deep-learning to capture the precise and accurate conformations of a peptide within minutes.

“There’s potential with this model to inform drug development through the design of peptides that act as binders.”

The study was recently published in the journal Nature Machine Intelligence.

A peptide’s role in the human body is directly linked to how it folds since its 3D structure determines the way it binds and interacts with other molecules.

“Peptides were the focus of the PepFlow model because they are very important biological molecules and they are naturally very dynamic, so we need to model their different conformations to understand their function,” said Philip M. Kim, the study’s principal investigator and a professor at the Donnelly Centre. “They’re also important as therapeutics, as can be seen by the GLP1 analogues, like Ozempic, used to treat diabetes and obesity.”

Peptides are also cheaper to produce than their larger protein counterparts, said Kim, who is also a professor of computer science in ��ɫֱ��’s Faculty of Arts & Science and a professor of molecular genetics in the Temerty Faculty of Medicine.

The new model expands on the capabilities of AlphaFold, the leading Google DeepMind AI system for predicting protein structure. It does this by generating a range of conformations for a given peptide. Taking inspiration from highly advanced physics-based machine learning models, PepFlow can also model peptide structures that take on unusual formations, including the ring-like structure that results from a process called macrocyclization. Peptide macrocycles are currently a highly promising venue for drug development.

“It took two-and-a-half years to develop PepFlow and one month to train it, but it was worthwhile to move to the next frontier beyond models that only predict one structure of a peptide,” Abdin said.

There are, however, limitations given that PepFlow represents the first version of a new model. The study authors noted a number of ways in which PepFlow could be improved, including training the model with explicit data for solvent atoms, which would dissolve the peptides to form a solution, and for constraints on the distance between atoms in ring-like structures.

Yet, even as a first version, the researchers say PepFlow is a comprehensive and efficient model with potential for furthering the development of treatments that depend on peptide binding to activate or inhibit biological processes.

“Modelling with PepFlow offers insight into the real energy landscape of peptides,” said Abdin.

The research was supported by the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada.

Common antibiotics carry small but serious risks of life-threatening drug reactions: Study

Christopher.Sorensen — Wed, 14 Aug 2024 12:51:57 +0000

Common antibiotics carry small but serious risks of life-threatening drug reactions: Study

Christopher.Sorensen Wed, 08/14/2024 - 08:51

Cutline

(photo by vorDa/Getty Images)

Misty Pratt

Topic

Sunnybrook Health Sciences

Subheadline

Researchers say physicians should consider prescribing lower-risk antibiotics for patients when clinically appropriate

Two classes of commonly prescribed oral antibiotics are associated with the greatest risk for severe drug rashes that can lead to emergency department visits, hospitalizations and even death, according to a study by researchers at ICES, Sunnybrook Research Institute and the ��ɫֱ��.

The study, published in the journal JAMA, found that sulfonamides (“sulfa drugs”) and cephalosporins were associated with the highest risk of reactions. The findings were based on a case-control study that used health-care data from ICES of adults 66 years or older who received a prescription for at least one oral antibiotic between 2002 and 2022 in Ontario.

Serious cutaneous adverse drug reactions (cADRs), or severe drug rash, are a group of rare but potentially life-threatening delayed reactions involving the skin and, often, internal organs. Some of these reactions carry mortality rates from 20 to 40 per cent. While many different classes of drugs can cause serious reactions, antibiotics are among the most commonly reported triggers.

The researchers say physicians should consider prescribing lower-risk antibiotics for patients when clinically appropriate.

“Clinicians have speculated that certain antibiotics carry greater risk for these severe reactions, but no study has ever confirmed these claims,” says Erika Lee, an allergist and a trainee with ICES and the Temerty Faculty of Medicine’s Eliot Phillipson Clinician-Scientist Training Program.

“Our objective was to explore the risk for cADRs in a population of older adults, who tend to receive disproportionately more antibiotic prescriptions than younger adults.”

Over the study period, 21,758 adults had an emergency department visit or hospitalization for a serious reaction following oral antibiotics and were matched with 87,025 controls who did not have a reaction.

“The good news is that most patients who visited the hospital with these reactions were discharged without being admitted, so that should be reassuring to providers and patients,” says Lee. “However, of those who were admitted to hospital with the most severe reactions, 20 per cent were treated in the ICU and five per cent of hospitalized patients died, which underscores the need for careful prescribing practices.”

The most commonly prescribed antibiotics were penicillins (29 per cent), followed by cephalosporins (18 per cent), fluoroquinolones (17 per cent), macrolides (15 per cent) nitrofurantoin (nine per cent) and sulfonamides (six per cent). Less commonly prescribed antibiotics were grouped together and accounted for seven per cent of prescriptions.

Other key findings include:

There were two antibiotic reaction-related hospital visits for every 1,000 antibiotic prescriptions dispensed
About one in eight patients who arrived at the emergency department with antibiotic-related reactions were hospitalized, likely because their reactions were more severe or because of concerns about potential complications
Twenty per cent of hospitalized patients with the most severe forms of reactions were treated in a critical care unit, and five per cent of those patients died

“While rare, these severe drug reactions can be life-threatening. Patients should be aware of rash, fever and other symptoms, which can start weeks after a prescription has been started and even after the course of antibiotics has stopped,” says David Juurlink, a staff internist and head of the division of clinical pharmacology and toxicology at Sunnybrook Health Sciences Centre, senior core scientist with ICES and professor in the department of medicine in the Temerty Faculty of Medicine.

“It’s also one more reason why antibiotics should be prescribed only when they’re truly needed.”

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��ɫֱ�� researchers develop RNA-targeting technology to precisely manipulate parts of human genes

Christopher.Sorensen — Thu, 08 Aug 2024 18:26:00 +0000

��ɫֱ�� researchers develop RNA-targeting technology to precisely manipulate parts of human genes

Christopher.Sorensen Thu, 08/08/2024 - 14:26

Cutline

From left to right: PhD student Jack Daiyang Li, Professor Benjamin Blencowe and Associate Professor Mikko Taipale (supplied images)

Anika Hazra

Topic

Donnelly Centre for Cellular & Biomolecular Research

Genes

Subheadline

“Our new tool makes possible a broad range of applications, from studying gene function and regulation to potentially correcting splicing defects in human disorders and diseases”

Researchers at the ��ɫֱ�� have harnessed a bacterial immune defence system, known as CRISPR, to efficiently and precisely control the process of RNA splicing.

The technology opens the door to new applications, including systematically interrogating the functions of parts of genes and correcting splicing deficiencies that underlie numerous diseases and disorders.

“Almost all human genes produce RNA transcripts that undergo the process of splicing, whereby coding segments, called exons, are joined together and non-coding segments, called introns, are removed and typically degraded,” said Jack Daiyang Li, first author on the study and PhD student of molecular genetics, working in the labs of ��ɫֱ�� researchers Benjamin Blencowe and Mikko Taipale at the Donnelly Centre for Cellular and Biomolecular Research in the Temerty Faculty of Medicine.

Exons from the same gene can be mixed and matched in various combinations to produce different versions of RNA, and consequently, different proteins. This process, called alternative splicing, contributes to the diverse expression of the 20,000 human genes that encode proteins, allowing the development and functional specialization of different types of cells.

However, it is unclear what most exons or introns do and the misregulation of normal alternative splicing patterns is a frequent cause or contributing factor to various diseases, including cancers and brain disorders. In addition, there is a lack of existing methods that allow for the precise and efficient manipulation of splicing.

The new study, published in the journal Molecular Cell, describes how a catalytically deactivated version of an RNA-targeting CRISPR protein, referred to as dCasRx, was joined to more than 300 splicing factors to discover a fusion protein called dCasRx-RBM25. This protein is capable of activating or repressing alternative exons in an efficient and targeted manner.

“Our new effector protein activated alternative splicing of around 90 per cent of tested target exons,” said Li. “Importantly, it is capable of simultaneously activating and repressing different exons to examine their combined functions.”

This multi-level manipulation will facilitate the experimental testing of functional interactions between alternatively spliced variants from genes to determine their combined roles in critical developmental and disease processes.

“Our new tool makes possible a broad range of applications, from studying gene function and regulation, to potentially correcting splicing defects in human disorders and diseases,” said Blencowe, principal investigator on the study, Canada Research Chair in RNA Biology and Genomics, Banbury Chair in Medical Research and a professor of molecular genetics at the Donnelly Centre and Temerty Medicine.

“We have developed a versatile engineered splicing factor that outperforms other available tools in the targeted control of alternative exons,” said Taipale, also principal investigator on the study, Canada Research Chair in Functional Proteomics and Proteostasis, Anne and Max Tanenbaum Chair in Molecular Medicine and associate professor of molecular genetics at the Donnelly Centre and Temerty Medicine. “It is also important to note that target exons are perturbed with remarkably high specificity by this splicing factor, which alleviates concerns about possible off-target effects.”

The researchers now have a tool in hand to systematically screen alternative exons to determine their roles in cell survival, cell-type specification and gene expression.

When it comes to the clinic, the splicing tool has potential to be used to treat numerous human disorders and diseases, such as cancers, in which splicing is often disrupted.

The research was supported by the Canadian Institutes of Health Research and the Simons Foundation.

Toronto Cannabis and Cannabinoid Research Consortium (TC3)

laurie.bulchak — Sat, 27 Jul 2024 17:19:13 +0000

Toronto Cannabis and Cannabinoid Research Consortium (TC3) laurie.bulchak Sat, 07/27/2024 - 13:19

URL

https://www.tc3.utoronto.ca

New study identifies two critical genes in pancreatic tumours

rahul.kalvapalle — Thu, 25 Jul 2024 14:46:33 +0000

New study identifies two critical genes in pancreatic tumours

rahul.kalvapalle Thu, 07/25/2024 - 10:46

Cutline

A team led by Daniel Schramek, a researcher at the Lunenfeld-Tanenbaum Research Institute (LTRI), Sinai Health and ��ɫֱ��'s Temerty Faculty of Medicine, identified two genes that are associated with fast-growing tumours in the pancreas (photo courtesy of Mount Sinai)

Jovana Drinjakovic

Topic

Sinai Health

Lunenfeld-Tanenbaum Research Institute

Cancer

Molecular Genetics

Subheadline

The findings mark a significant step forward in research on pancreatic cancer, a disease that has seen little progress in treatment options

��ɫֱ�� researchers have identified two genes that play a critical role in tumour growth in the pancreas – findings that have significant implications for understanding and treating pancreatic cancer.

The tumour suppressor genes USP15 and SCAF1 were discovered by a research team led by Daniel Schramek, a senior investigator at the Lunenfeld-Tanenbaum Research Institute (LTRI) and deputy director of discovery research and Tony Pawson Chair in Cancer Research at Sinai Health.

The team found that people who have mutations in these genes are more likely to develop fast-growing tumours – but these tumours are also more susceptible to chemotherapy. The findings, described in a study published in Nature Communications, mark a significant step forward in research on pancreatic cancer, a disease that has seen little progress in treatment options.

“While mutations in USP15 and SCAF1 make tumours more aggressive, they also sensitize tumours towards standard chemotherapy,” says Schramek, who is also an associate professor in the department of molecular genetics and Canada Research Chair in functional cancer genomics at the Temerty Faculty of Medicine.

“And that means that you could stratify patients and they should have a better response to treatment.”

The project was spearheaded by Sebastien Martinez, a former postdoctoral fellow at LTRI who is now a senior scientist at Centre de Recherche en Cancérologie de Lyon (CRCL) in France.

Pancreatic cancer continues to have few treatment options with devastatingly low survival rates, under five years post-diagnosis. According to one estimate, pancreatic cancer could be the second leading cause of cancer deaths in the United States by 2040.

Schramek's team achieved their breakthrough by leveraging advances in genomic medicine, specifically tumour DNA sequencing, to identify mutations and genome editing technologies.

“Sequencing tumours allows you to find the genes that are affected and use that knowledge to develop treatments. But the problem is that every cancer has a plethora of mutations, and not all of them are disease-causing,” says Schramek.

Cancers often feature common mutated genes in many patients, along with hundreds of less frequent mutations that appear in a smaller subset. While mutations in USP15 and SCAF1 were found in less than five per cent of patients, their effects on cancer remained unclear.

Traditionally, tumour suppressor genes have been pinpointed by sequentially deleting genes in cancer cell lines and noting which deletions increase cell growth. However, these cell-based studies don't replicate the tumour's natural environment and interactions with the immune system, which are crucial for cancer progression. This likely explains why previous screens overlooked USP15 and SCAF1.

A few years ago, Schramek's team developed a genome editing approach enabling them to remove hundreds of genes simultaneously from individual cells. This method helps identify genes that, when absent, trigger cancer in the natural body environment.

Utilizing this technology, the Schramek lab targeted 125 genes recurrently mutated in patient pancreatic tumours and pinpointed USP15 and SCAF1 as crucial tumor suppressors and potentially prognostic factors for chemotherapy response.

It just so happens that these genes are also absent in about 30 per cent of patients due to common genomic rearrangements in cancer.

This finding indicates that as many as a third of pancreatic patients who lack these genes might benefit from chemotherapy and have better outcomes.

“Historically, mutations in USP15 and SCAF1 would have been considered less important because they are not found in many patients,” Schramek says. “Our work shows that it is critical that we understand the functional consequences of these rare mutations as they can reveal new biology and therapeutic opportunities”

Anne-Claude Gingras, director of the Lunenfeld-Tanenbaum Research Institute and vice-president of research at Sinai Health, says the study “represents an important step forward in our understanding of the genes involved in pancreatic cancer.

“It also shows how a cutting-edge technology developed at Sinai Health is enabling new discoveries with the potential to create benefits to patients.”

This research was supported by funding from the Ontario Institute of Cancer Research, Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Foundation, Terry Fox Research Institute, Canadian Cancer Society Research Institute, Pancreatic Cancer Canada and the Canadian Institute of Health.

Study points to improved detection of thyroid cancer

Christopher.Sorensen — Thu, 04 Jul 2024 20:22:19 +0000

Study points to improved detection of thyroid cancer

Christopher.Sorensen Thu, 07/04/2024 - 16:22

Cutline

(photo by Basak Gurbuz Derman/Getty Images)

Gabrielle Giroday

Topic

Sinai Health

Cancer