Eileen Hoftyzer

PhD student's radiopharmaceutical to play key role in clinical trial for lung cancer treatment

rahul.kalvapalle — Tue, 26 Nov 2024 20:59:25 +0000

PhD student's radiopharmaceutical to play key role in clinical trial for lung cancer treatment

rahul.kalvapalle Tue, 11/26/2024 - 15:59

Cutline

Stephanie Borlase developed a radiopharmaceutical, which will be used during a clinical trial at Sunnybrook Health Sciences Centre, to track delivery of immunotherapy drugs across the blood-brain barrier (photo by Dana Thompson)

Eileen Hoftyzer

Topic

Breaking Research

Sunnybrook Health Sciences Centre

Graduate Students

Leslie Dan Faculty of Pharmacy

Subheadline

The compound developed by �鶹��Ƶ's Stephanie Borlase will be used to track delivery of immunotherapy drugs to metastases in the brain

A radiopharmaceutical developed by University of Toronto PhD student Stephanie Borlase is poised to play a key role in a clinical trial that could inform improvements to lung cancer treatment.

The trial at Sunnybrook Health Sciences Centre, planned for 2025, will test whether ultrasound can disrupt the blood-brain barrier and increase uptake of immunotherapy into brain metastases – tumours caused by cancer cells spreading to the brain from elsewhere in the body.

Although immunotherapy has shown potential as a treatment for lung cancer, it is not able to cross the blood-brain barrier. Borlase’s radiopharmaceutical, which she developed as part of her doctoral research at the Leslie Dan Faculty of Pharmacy, will be used to track delivery of immunotherapy drugs to brain metastases with a PET (positron emission tomography) scan.

“This project provides me with the opportunity to learn different aspects of research and be on the forefront of patient treatments,” says Borlase. “It is such an amazing opportunity to be able to see what is happening in the hospital with current patients and clinical trials and know that my research is actually getting to patients.”

Borlase completed her undergraduate and master’s degrees at the University of Manitoba, before seeking out a PhD program where she could conduct research that could potentially be translated into therapies for patients with hard-to-treat cancers.

In 2022, she began her PhD with Professor Raymond Reilly, director of the Centre for Pharmaceutical Oncology (CPO), whose research focuses on developing radiopharmaceuticals to image and treat cancer.

By attaching radioactive isotopes to highly targeted agents, radiopharmaceuticals allow clinicians to image tumours through scans and deliver therapeutic doses of radiation directly to the tumour.

Borlase has been working towards pairing the immunotherapy drug pembrolizumab (also known by the brand name Keytruda) with a radioactive isotope that can be imaged by PET – resulting in a radiopharmaceutical that could allow physicians to determine whether the therapy enters the brain and concentrates better in tumours after the application of focused ultrasound.

For the first two years of her PhD, Borlase worked in the CPO’s Good Manufacturing Practices facility to prepare the new radiopharmaceutical for clinical trials, optimizing and formulating the drug in a quality suitable for use in humans, and testing it in pre-clinical models.

Reilly says that this is an exceptional experience for a graduate student. “One of the greatest impacts and rewards of pharmaceutical sciences research is to see your work advanced to a clinical trial to make a difference in patient outcomes, which Stephanie has this wonderful opportunity to do,” he says.

“Not only is she developing the radiopharmaceutical, but she will be working closely with the oncologists and imaging specialists to design and conduct the trial and will get first-hand experience in seeing the results of her PhD research in the PET images of the patients in the trial.”

The trial follows on the heels of another study in which clinicians and scientists at Sunnybrook used a radiopharmaceutical provided by Reilly’s team to track the delivery of a breast cancer drug to brain metastases, resulting in the first evidence that the technique improved uptake of the drug.

For her part, Borlase says she hopes the trial will lead to better therapies for a form of cancer that is notoriously difficult to treat.

“I always hope that researchers can develop new treatments for cancer because it is such a terrible disease that is never going to disappear. Even if we cannot completely cure the brain metastases, we can work to prolong survival to give these individuals more time with their families and friends,” says Borlase, who recently received a Research Training Award from the Canadian Cancer Society and Brain Canada Foundation.

“It's such a rare opportunity for PhD students to be able to work with clinician-scientists or oncologists and actually see their research translate into a clinical setting, so the fact that I am able to do this is incredible.”

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 �鶹��Ƶ, is based on three key biomarkers (photo by FG Trade/Getty Images)

Eileen Hoftyzer

Topic

Breaking Research

Department of Medicine

Temerty Faculty 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 University of Toronto 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 �鶹��Ƶ’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.

‘Give yourself grace’: Pharmacy grad from Nigeria reflects on �鶹��Ƶ journey

rahul.kalvapalle — Thu, 13 Jun 2024 13:46:18 +0000

‘Give yourself grace’: Pharmacy grad from Nigeria reflects on �鶹��Ƶ journey

rahul.kalvapalle Thu, 06/13/2024 - 09:46

Cutline

Theodora Udounwa completed her �鶹��Ƶ undergraduate degree in just two years before studying to be a pharmacist at the Leslie Dan Faculty of Pharmacy (photo by Steve Southon)

Eileen Hoftyzer

Topic

Our Community

Convocation 2024

Leslie Dan Faculty of Pharmacy

St. Michael's College

Subheadline

At age 21, Theodora Udounwa is graduating with a Doctor of Pharmacy degree

Theodora Udounwa was 15 years old when she left her family in Nigeria and traveled to Canada to begin a bachelor of science at the University of Toronto.

Born and raised in Abuja, Udounwa graduated from high school at an unusually young age due to a combination of an early start to kindergarten and skipping a grade due to outstanding academic performance.

It was a trend that would continue at �鶹��Ƶ. After only two years as an undergraduate, specializing in pharmacology and biomedical toxicology with a minor in physiology, Udounwa began her doctor of pharmacy (PharmD) program at the Leslie Dan Faculty of Pharmacy.

“Pharmacy was always the plan. I enjoyed pharmacology greatly, but I was also interested in patient care, and I saw pharmacy as a bridge between applying those theoretical principles to patient care,” says Udounwa, who graduated with her PharmD last week at only 21 years old. “There are also a lot of career options in addition to patient care, like academic and research, that I thought would be a good fit for me.”

Like many youths in Nigeria, Udouwna attended boarding school during middle school and high school – an experience that stood her in good stead when she moved into St. Michael’s College residence, where she was younger than her peers. The proximity to her older sister – who attended university in nearby Hamilton – and an aunt in Ajax meant she was able to spend holidays with family members in the area.

Udouwna also took it upon herself to get involved with student groups such as the Nigerian Students’ Association, where she was able to meet students from her home country and share her culture.

Starting the PharmD program during the first year of the COVID-19 pandemic, Udounwa grasped the opportunity to contribute to the public health response and strengthen her training, delivering more than 1,600 COVID-19 vaccinations as well as numerous flu shots at Discovery Pharmacy pop-up clinics.

She also completed rotations at Shoppers Drug Mart, the Hospital for Sick Children, Toronto General Hospital, St. Michael’s Hospital (Unity Health Toronto), the outpatient pharmacy at the Centre for Addiction and Mental Health (CAMH) and the Canadian Armed Forces.

All along, she stayed involved with student groups, holding several positions with the Black Pharmacy Students’ Association and the �鶹��Ƶ chapter of the Canadian Association of Pharmacy Students and Interns (CAPSI).

She says one of the highlights of her time at �鶹��Ƶ was attending CAPSI’s 2023 professional development week in Saskatoon, where she supported 16 �鶹��Ƶ delegates and took advantage of several educational and networking opportunities. “It was great to connect with students from other pharmacy schools, and I appreciated the opportunity to expand my professional skills and clinical knowledge,” she says. “We also had the chance to visit an Indigenous heritage site, Wanuskewin, and learn about Indigenous history and culture, which was very enriching.”

Udounwa’s involvement in extracurricular activities earned her numerous accolades including a �鶹��Ƶ Student Leadership Award and a Canadian Pharmacists’ Association Centennial Leadership Award. “Devoting time to volunteering and participating in student groups has enabled me to facilitate macro-level changes that directly impact the pharmacy student community. It has also fostered my personal and professional growth through forming connections with and learning from students and practice leaders," Udounwa said upon receiving her Student Leadership Award earlier this year.

Looking ahead, Udounwa says she’s keeping her options open but envisions working directly with patients in some capacity. Her next step: an industry residency at pharma giant Novo Nordisk's medical affairs and strategic operations department.

Having navigated the challenges of moving to a new country for university and experiencing a new culture, Udounwa says she would advise incoming university students to be kind to themselves as they forge their journey.

“This is a pivotal moment in our careers; be patient and give yourself grace as you go through the process and navigate through that uncertainty to the next great opportunity.”

'Iterate, adapt and accelerate': �鶹��Ƶ researcher on working at the crossroads of science and business

Christopher.Sorensen — Fri, 08 Mar 2024 14:05:30 +0000

'Iterate, adapt and accelerate': �鶹��Ƶ researcher on working at the crossroads of science and business

Christopher.Sorensen Fri, 03/08/2024 - 09:05

Cutline

Christine Allen, a professor in �鶹��Ƶ’s Leslie Dan Faculty of Pharmacy, has launched several startups over the course of her career and is a champion of women in STEM (photo by Steve Southon)

Eileen Hoftyzer

Topic

Our Community

Entrepreneurship

Leslie Dan Faculty of Pharmacy

Research & Innovation

Startups

Subheadline

“As an entrepreneur, you can’t stop thinking about the market, your customers’ problems and how you will solve them”

Making the leap from scientist to entrepreneur requires creativity, determination and resilience – not to mention an acute understanding of the real-world need for the innovative technology or idea in question.

Christine Allen, a professor in the University of Toronto’s Leslie Dan Faculty of Pharmacy and who has launched several startups, says the last part of the equation is particularly important.

“It’s not just about whether you have an interesting idea,” says Allen, an expert in drug formulation and development. “You also have to identify a use case for your technology that addresses the problem better than the existing technology and successfully do everything it takes to get the technology to the patient.

“You need to have a clear target market and differentiated value proposition.”

Allen has focused on turning laboratory discoveries into clinical tools since the early days of her career. Following her postdoctoral training at the BC Cancer Agency, she worked as a scientist at Celator Pharmaceuticals before moving back to academia to take a role at �鶹��Ƶ’s Leslie Dan Faculty of Pharmacy. Since setting up her �鶹��Ƶ lab, she has worked closely with the pharmaceutical industry and clinicians to license her patented technologies and support the development of new drugs.

“Since I started at the University of Toronto, I’ve always worked with companies,” she says. “One of the reasons is that I really want to work on research that will result in a new drug or technology or device that can be used in the real world or in patients.”

She has also founded startup companies to advance promising technologies. That includes Nanovista to develop nanotechnology that illuminates tumours to allow for precise image-guided surgery and cancer therapy. The company is currently raising capital to enter a Phase 1 clinical trial.

Listen to Christine Allen discuss her work on the I'm Pharmacy Podcast

Then, in 2023, Allen partnered with Alán Aspuru-Guzik, a professor in �鶹��Ƶ’s departments of chemistry and computer science in the Faculty of Arts & Science who is an expert in artificial intelligence, to build Intrepid Labs. Intrepid has developed a proprietary technology that uses machine learning and robotics to accelerate drug development through better, faster drug formulation.

The company is the first startup to emerge from the Acceleration Consortium, a �鶹��Ƶ institutional strategic initiative led by Aspuru-Guzik that uses self-driving labs to speed the discovery of materials and molecules needed for a sustainable future.

In drug development, Allen says, focusing on the needs of patients and clinicians is paramount.

“As an entrepreneur, you can’t stop thinking about the market, your customers’ problems and how you will solve them,” she says. “The path is not a straight line. You need to iterate, adapt and accelerate.”

Pauric Bannigan started as a postdoctoral fellow in Allen’s lab before becoming the lab’s senior research associate and launching Intrepid alongside Allen, Aspuru-Guzik and �鶹��Ƶ alumnus Riley Hickman. He says that launching a company requires effort and resilience, but the team’s commitment to the technology helps them push through the challenges.

“My time in Christine’s lab provided a unique vantage point on the pharma and biotech ecosystem, laying a strong foundation for navigating the entrepreneurial world. Despite this background, the shift to a startup led to many new challenges – from recalibrating our research for market needs to understanding the intricacies of intellectual property and direct customer engagement,” he says.

“Looking ahead, I'm optimistic. Our team is committed, and our technology has the potential to make a significant impact. As we continue to grow and evolve, the experiences gained from each challenge only strengthen our resolve and commitment to success.”

Longstanding interest in women’s health and women in STEM

In her lab, Allen continues to work with pharmaceutical companies to develop new formulations. In recent years, she has been working with Jazz Pharmaceuticals (which now owns Celator) to develop a new therapy for ovarian cancer – a field of research that she is particularly interested in.

“Women’s cancer is something that’s really important to me, particularly ovarian cancer because standard of care hasn’t changed much over time,” she says.

Allen will be presenting her work as the keynote speaker at a women’s health session at the 2024 Controlled Release Society (CRS) annual meeting.

Allen was invited to speak at the session by Hagar Labouta, a scientist at Unity Health Toronto and an assistant professor in the Leslie Dan Faculty of Pharmacy. They first met through the CRS’s Women in Science Committee, which hosts virtual and in-person events for women in the society and provides annual awards.

Allen also organizes �鶹��Ƶ’s Women in STEAM: Leading and Reading book club, which invites students and faculty from across the university and hospital community to discuss books, as well as issues and experiences they face as women.

“Women experience certain challenges that often only resonate fully when shared with other women. It's comforting to know others have navigated similar issues successfully, reinforcing the belief that you can overcome these challenges, too,” Allen says. “Initiatives like the book club and the Women in Science group foster a sense of community. They ensure individuals feel heard, seen and that they belong – a sentiment that might be hard to find in large organizations.”

Major shift in acceptance of entrepreneurship

Allen says she has seen attitudes about entrepreneurship shift during more than 20 years at the university – and that there is now greater support for scientists and trainees looking to launch startups and commercialize their research.

Allen has been on the forefront of this shift, taking on leadership roles in the university and in industry, including a one-year appointment at adMare Bioinnovations, an organization that helps support Canadian life science companies and researchers.

Her commitment to translational research and commercialization carries over to her trainees. Bannigan notes that Allen’s connections within industry offer trainees unique learning and networking opportunities that help them gain a deeper understanding of entrepreneurship and commercialization.

“Christine always encourages interdisciplinary collaboration, allowing members to work on projects that merge fields such as pharmaceutical science and data science,” he says. “This interdisciplinary approach is crucial for innovation and creates a positive atmosphere where ideas and knowledge are freely shared, which often leads to the development of innovative solutions to complex problems.”

Allen has recently been recognized with two high-profile awards: the Community Service Award from Life Sciences Ontario and the Julia Levy Award from the Society of Chemical Industry, which recognizes successful commercialization of innovation in Canada.

“I feel very proud of the translational work that I’ve done, whether it’s the technologies in my own lab or the drugs I’ve helped formulate and move closer to translation and commercialization,” Allen says.

“When you put a lot of energy and effort into something and people notice, it means a lot. I have been well supported at �鶹��Ƶ and in this broad community of biotech, pharma and innovation organizations. Being recognized by people that you really care about means so much.”

Researchers examine the effects of anti-HIV drugs on pregnancy

rahul.kalvapalle — Fri, 08 Dec 2023 20:13:19 +0000

Researchers examine the effects of anti-HIV drugs on pregnancy

rahul.kalvapalle Fri, 12/08/2023 - 15:13

Cutline

Pharmaceutical sciences master's degree student Teresa Bennett (left) and Professor Reina Bendayan are investigating whether first-line anti-HIV drugs can inhibit folate uptake in the placenta during pregnancy (photos by Steve Southon)

Eileen Hoftyzer

Topic

Breaking Research

Temerty Faculty of Medicine

Leslie Dan Faculty of Pharmacy

University Health Network

Subheadline

Study will provide important information on the impact of critical antiretroviral drugs on fetuses

In many developing countries, low-cost antiretroviral drugs have helped extend the lives of people living with human immunodeficiency virus (HIV), as well as prevent transmission of the virus from pregnant women to babies.

These treatments may not be free of risk. A few years ago, a high-profile paper alerted the international community that babies in Botswana that were exposed to the anti-HIV drug dolutegravir in utero had an increased risk of birth defects.

While subsequent studies have suggested much lower risks amid concerns that pausing use of the drug could have consequences for HIV transmission in low-resource countries, researchers at �鶹��Ƶ and its partner hospitals are continuing to investigate.

“The administration of the drugs to the mother prevents the transmission of infection to the newborn, and there’s no question that this treatment is extremely effective in eradicating the infection in newborns, so there is a great benefit,” says Reina Bendayan, professor at the University of Toronto’s Leslie Dan Faculty of Pharmacy whose research has long focused on HIV antiretroviral treatments – specifically examining how specialized proteins called transporters move these drugs from blood into tissues.

“However, a number of problems have been reported in the clinic in some of the children that have been exposed to the anti-HIV drugs.”

With the support of the Canadian Institutes of Health Research, Bendayan and co-principal investigator Lena Serghides, senior scientist at the Toronto General Hospital Research Institute at the University Health Network and associate professor in the department of immunology at the Temerty Faculty of Medicine, will study membrane transport proteins, including folate transporters, that regulate the distribution and delivery of anti-HIV drugs to the fetus – not just dolutegravir but also newer drugs of the same class.

In recent years, Bendayan’s lab has looked at transport proteins that move the nutrient folate into the placenta and fetus during pregnancy and how interactions with these transport proteins could contribute to folate deficiency, which can result in neurodevelopmental defects in children.

So when her team saw the research about a potential link between dolutegravir and birth defects, they immediately wondered whether these drugs might be interacting with the folate transporters and inhibiting folate uptake in the placenta. Their initial studies identified a potential interaction.

The team is now looking to investigate the potential interaction of first-line anti-HIV drugs during pregnancy and further examine folate levels in the fetus. “We are looking at biodistribution of these drugs, but at the same time we are investigating potential fetal toxicities that may result from these drugs,” Bendayan says.

Using human cells, placenta tissue and research models, the researchers are examining how expression and location of transport proteins in the placenta change through gestation, the impact this has on how much of the drug crosses into the placenta and whether this results in any neurodevelopmental defects.

They’re also examining whether male and female fetuses differ in their membrane transport expression, drug concentrations and toxicity levels.

“By improving our basic understanding of how these transporters change throughout pregnancy, our findings could have broader implications, providing insights about safety and fetal development of a wide spectrum of medications used in pregnancy,” says Serghides.

Professor Reina Bendayan (left) and pharmaceutical sciences master's student Teresa Bennett (right).

Teresa Bennett, a master’s student in the department of pharmaceutical sciences at the Leslie Dan Faculty of Pharmacy and recipient of a Canada Graduate Scholarship, is running experiments and collecting data for the research as part of her thesis project, which she says combines her two academic interests – newborn and fetal health and HIV care.

“Before a drug is approved for use, it has to go through rigorous testing, but oftentimes there isn’t as much research done on the pregnant population and how it will impact them and their baby,” says Bennett, who began working in Bendayan’s lab in 2022 after conducting undergraduate research on HIV-related stigma. “I’m hoping this research will further inform guidelines so that we can keep the pregnant population in a controlled HIV status throughout their pregnancy, but also keep the baby healthy.”

Bendayan agrees that the study will provide important information on the impact of these critical drugs on fetuses, which will help guide treatment decisions for pregnant people with HIV.

“We really want to clarify whether the newer drugs in this class would potentially be a better choice. These haven’t been in the clinic very long, so we don’t know yet, and we hope our studies can shed some light on that,” says Bendayan.

“We hope that this research will provide a greater understanding of the potential toxicity implications of these specific antiretroviral drugs so that we have better guidance on which antiretroviral drugs physicians should recommend to their patients.”

Study suggests two-pronged approach to treatment for neurodegenerative disease

Christopher.Sorensen — Mon, 28 Aug 2023 14:08:07 +0000

Study suggests two-pronged approach to treatment for neurodegenerative disease

Christopher.Sorensen Mon, 08/28/2023 - 10:08

Cutline

Shelley Forrest, a neuropathologist and research associate in the lab of Gabor Kovacs, co-authored a study that uncovered the subtypes of brain cells associated with the production of a key protein involved in the development of a neurodegenerative disease (supplied image)

Eileen Hoftyzer

Topic

Breaking Research

Temerty Faculty of Medicine

Tanz Centre for Research in Neurodegenerative Diseases

Research & Innovation

Researchers at the University of Toronto’s Tanz Centre for Research in Neurodegenerative Diseases have used novel techniques to uncover which subtypes of brain cells express genetic material that produces tau, a key protein involved in the development of the neurodegenerative disease progressive supranuclear palsy (PSP).

The study, published recently in the journal Acta Neuropathologica, suggests that a two-pronged approach to treatment that targets two key mechanisms in disease development may be more effective than current methods.

“This study uses a novel methodology to show that the glial cells – the supporting brain tissue – can produce tau themselves and become diseased without taking up tau from nerve cells. Therefore, glial cells are more important in disease pathogenesis than previously assumed,” says Gabor Kovacs, investigator at the Tanz Centre and a professor in the Temerty Faculty of Medicine’s department of laboratory medicine and pathobiology.

“This study also shows that RNA expression of tau, thus the production of tau, is preserved during disease and providing a continuous supply of tau, which should be kept in mind in therapy development.”

One of the most common features of neurodegenerative diseases such as PSP and Alzheimer’s disease is the accumulation of misfolded tau protein in neurons and their supporting cells, impairing the function of these cells.

Researchers have long debated which brain cells express the gene MAPT, which codes for tau. For decades, the dominant view has been that neurons express MAPT RNA, but glial cells do not.

Shelley Forrest, a neuropathologist and research associate with Kovacs’ team, says that neuropathologists have observed that glial cells contain tau aggregates, but there was no solid evidence about where it was coming from.

“In these neurodegenerative diseases, we find pathological tau aggregates in the glia, so there’s always been active debate on why tau pathology accumulates in glia, and whether it’s produced by neurons and taken up by glia or whether glia can make it themselves independently,” says Forrest.

The research team, which included collaborators in Australia and Dubai, examined brain tissue samples from three patients who had PSP and three who did not. Having access to these post-mortem patient samples – which Forrest describes as “the most generous gift anyone can give” – allowed the researchers to have a more complete and realistic view of the RNA expression in different brain cell types compared to using animal models or cell cultures.

The team used innovative RNAscope technology to visualize RNA molecules under the microscope, as well as single nucleus RNA sequencing, in order to map RNA expression in different brain regions and different types of brain cells. The patient samples combined with the new technology allowed the researchers to visualize for the first time where MAPT RNA is expressed in the brain.

The team found that different brain regions and brain cells differ in the amount of MAPT RNA they express. And, importantly, they identified that glial cells do express MAPT RNA – providing the first solid evidence of its presence in these cells. This means that glial cells are not only taking up misfolded tau produced by neurons, but are also making it themselves.

“We’ve long had this suspicion, but now we’ve been able to get the evidence to demonstrate that this is the case,” says Forrest. “How and why tau accumulates in glia in PSP is not entirely clear, but our study highlights two novel mechanistic pathways for the cell-to-cell transmission of misfolded tau and accumulation in the brain, which is an exciting result.”

The study results suggest that a two-pronged approach to therapy – targeting both the misfolded tau protein and MAPT RNA expression – could be the best strategy for treating PSP and similar diseases.

“Because we’re proposing two different pathways for the pathogenesis of the disease, if you only focus on one, you’re just getting half the picture,” says Forrest. “If you block one pathway, it will just proceed with the other pathway. You’ve got to block both.”

Kovacs’ team will now use similar techniques to study this same question in other neurodegenerative diseases. They will also follow up on their results to understand RNA expression across the different brain regions.

“Our team is one of the first to use these techniques in neurodegenerative-diseased human brain samples. We will now expand this examination to other diseased proteins and map how changes in the tau RNA expression affect expression of crucial genes at the cellular level, focusing on glial cells,” Kovacs says.

“Ultimately, this work will inform basic researchers to focus on glial cells – not just neurons – when trying to unravel the pathogenesis of PSP, and will inform therapy developers to not only remove misfolded tau as they currently do, but also decrease production of normal tau using RNA-based therapies.”

Radiopharmaceuticals offer promise to image – and treat – cancer

Christopher.Sorensen — Wed, 16 Aug 2023 18:09:23 +0000

Radiopharmaceuticals offer promise to image – and treat – cancer

Christopher.Sorensen Wed, 08/16/2023 - 14:09

Cutline

(photo by Johnny Greig/Getty Images)

Eileen Hoftyzer

Topic

Our Community

Cancer

Leslie Dan Faculty of Pharmacy

Research & Innovation

Subheadline

$24-million cross-Canada grant will support development of radiopharmaceuticals from discovery to use in the health-care system

Nuclear medicine was first developed in the 1950s as a cancer treatment before shifting to primarily being used as a diagnostic tool, using tiny amounts of radioactive substances to image different parts of the body.

Now, nearly three quarters of a century later, the field is coming full circle as researchers like Raymond Reilly, a professor in the University of Toronto’s Leslie Dan Faculty of Pharmacy, explore options for new cancer therapies.

Reilly is a leader in developing radiopharmaceuticals that combine radioactive isotopes with highly specific targeting agents to precisely deliver radiation to tumours. His work focuses specifically on radiopharmaceuticals that have “theranostic” properties – useful for both the imaging and treatment of cancer.

Professor Raymond Reilly, director of the Centre for Pharmaceutical Oncology at the Leslie Dan Faculty of Pharmacy (photo by Steve Southon)

“Radiopharmaceuticals are unique in that you can use the radiopharmaceutical for diagnostic imaging purposes, but you can also use the same agent, sometimes at a higher dose or labelled with a different radioisotope, to treat the cancer,” says Reilly. “And you can then use that same radiopharmaceutical to image the patient again after treatment to see if that patient responded to the treatment.”

Cancer researchers and pharmaceutical companies have become more interested in the field after two radiopharmaceuticals were developed and used to successfully treat neuroendocrine cancer and prostate cancer.

“These are the vanguard or leading edge of this type of radiopharmaceuticals, but they are really just the tip of the iceberg of what is possible with radiopharmaceuticals,” says Reilly. “Radiopharmaceuticals used to be a specialized area of medical research with a small group of dedicated scientists, but it’s starting to emerge as a new cancer treatment that could overcome resistance to other treatments.”

However, Reilly explains that the current availability of radioisotopes suitable for cancer therapy is extremely limited. For example, the world supply of one particularly effective isotope called actinium-225 would only be enough to treat a few thousand cancer patients.

A new $24-million grant aims to address this shortage. The New Frontiers Research Fund (NFRF), a highly competitive federal research grant to support research that will realize transformational change for a major challenge, is supporting a large cross-Canada team that will develop rare isotopes for cancer from discovery to their integration into the health-care system.

The project is led by François Bénard, an internationally recognized leader in nuclear medicine, at the BC Cancer Agency, and includes 16 co-investigators across Canada, including Reilly, who is the sole �鶹��Ƶ co-investigator on the project. The team includes researchers at TRIUMF, Canada’s world-leading particle accelerator centre in British Columbia that creates medical isotopes, chemists who will study ways of attaching the isotopes to targeting agents and clinical trials specialists who will study the radiopharmaceuticals for the first time in patients. Health economists on the team will try to understand how best to implement the radiopharmaceuticals into Canada’s health-care system.

Reilly is leading one component of the research that aims to develop radiopharmaceuticals to image and treat recurrence of head and neck cancer. His team is collaborating with researchers at University Health Network to test the new radiopharmaceuticals in preclinical models and find ways to detect recurrence early so that it can be effectively treated with radiopharmaceuticals.

Radiopharmaceuticals have potential to treat breast and brain cancers

In addition to the work being done through the NFRF project, Reilly and his team have made significant advances with other radiopharmaceuticals for cancer treatment.

For example, Reilly’s team developed a radiolabelled version of the breast cancer drug Herceptin, which was used in a small clinical trial that examined its treatment for brain metastases of breast cancer. In the trial, the researchers studied whether high-intensity focused ultrasound would allow Herceptin to more effectively cross the blood-brain barrier and reach the tumour. Reilly’s radiopharmaceutical was key to imaging if – and where – the drug accumulated in the brain.

His team has also been working on developing radiation nanomedicines, which combine radiopharmaceuticals and nanotechnology. They have recently developed radiolabelled gold nanoparticles that, in preclinical models, are able to precisely deliver radioisotopes to brain tumour cells and kill them without harming normal tissue. They have had promising results with these first-generation radiolabelled nanomedicines and are continuing to develop and improve them.

As the field grows from a niche specialty to a more widely studied potential cancer treatment, Reilly says he is excited about the potential for radiopharmaceuticals to have a significant impact in improving patient outcomes.

“One of the transformations that has emerged in recent years is a tremendous resurgence of interest in radiopharmaceuticals for cancer treatment – not just for imaging – and now combining them into this theranostic concept,” says Reilly. “The New Frontiers research grant will link nuclear medicine specialists and radiopharmaceutical scientists across Canada to develop the next generation of radiopharmaceuticals that will have this dual purpose.

“It’s a really exciting time in radiopharmaceutical research.”

New autonomous lab at University of Toronto to improve drug formulation

siddiq22 — Fri, 14 Jul 2023 20:09:01 +0000

New autonomous lab at University of Toronto to improve drug formulation

siddiq22 Fri, 07/14/2023 - 16:09

Cutline

From left: PhD trainee Zeqing Bao, Professor Christine Allen, Allen Lab Director of Research and Partnerships Pauric Bannigan (photo by Steve Southon)

Eileen Hoftyzer

Topic

Breaking Research

Acceleration Consortium

drug development

Institutional Strategic Initiatives

self-driving labs

Artificial Intelligence

Entrepreneneurship

Leslie Dan Faculty of Pharmacy

machine learning

Research & Innovation

Subheadline

Facility at Leslie Dan Faculty of Pharmacy is one of six at �鶹��Ƶ being funded by $200-million grant to Acceleration Consortium

A new autonomous lab being built in the University of Toronto's Leslie Dan Faculty of Pharmacy will help to design and optimize formulations that will improve bioavailability, stability and efficacy of a variety of drugs.

Christine Allen, a professor in the faculty whose research focuses on drug development and disease diagnostics, is co-leading the lab with Frank Gu, a professor in the department of chemical engineering and applied chemistry in the Faculty of Applied Science & Engineering.

“I see huge potential for artificial intelligence (AI), machine learning and automation in pharmaceutical sciences, for formulations and beyond,” says Allen, an expert in drug formulations.

“The world is finally understanding the impact of formulation technology and how powerful it is. Now we can marry that technology with AI and machine learning, so we’re kind of unstoppable.”

The new facility is known as a 'self-driving' lab because it uses AI, automation and advanced computing to test different combinations of materials and iteratively develop the best formulations. This approach will allow researchers to evaluate a much larger number of materials, significantly reducing both the cost and time required to identify a new drug formulation.

Allen explains that formulation scientists are often working under tight time constraints to get a product to market by deadline, and the final formulations are the best that can be done with the time available – but are not necessarily the best possible option.

“We’re providing a solution to that – accelerating development while looking for the best formulation,” says Allen, whose team worked in collaboration with Professor Alán Aspuru-Guzik’s research group to develop a prototype of the self-driving lab last year.

The self-driving lab at the Leslie Dan Faculty of Pharmacy is one of six being built at �鶹��Ƶ through a $200-million Canada First Research Excellence Fund grant to the Acceleration Consortium, a global network of government, industry and academic researchers accelerating the discovery of materials and molecules needed for a sustainable future.

Researchers say the self-driving lab will help the pharmaceutical industry improve efficiency in drug development and production (photo by Steve Southon)

Allen played a key role in launching the Acceleration Consortium during her time as associate vice-president and vice-provost, strategic initiatives.

As a co-lead on the project, Gu is bringing his expertise in nanotechnology engineering to develop high-quality, precise formulations that use nanotechnology to improve the delivery, bioavailability and efficacy of drugs.

“Nanotechnology engineering has revolutionized the pharmaceutical industry, and its potential applications in a self-driving lab are both imminent and paradigm-shifting,” Gu says.

“By harnessing the power of nanotechnology in a self-driving lab for pharmaceutical formulations, my lab is working with Professor Allen’s team to unlock many advantages that will transform drug development, formulation, modular manufacturing and patient care.”

Allen says that the lab's strong collaboration between pharmaceutical scientists and computer scientists also provides unique educational opportunities for trainees that will provide them with key skills needed for a career in the pharmaceutical industry.

“The trainees are experts in both fields – this is where the future is going, and that to me is the power in all of this. It is true interdisciplinary collaboration,” Allen says. “The trainees are gaining knowledge, expertise and experience, and they are then able to secure exciting positions in industry and be leaders in the field.”

Last year, Allen took a leave of absence from the university to take on a leadership role with adMare Bioinnovations, an organization that helps support Canadian life science companies and researchers. She has now returned to the Leslie Dan Faculty of Pharmacy full-time and brings back a wealth of new experience in entrepreneurship that she plans to apply to her research and the work of the Acceleration Consortium.

To that end, Allen is also chairing the Acceleration Consortium's committee on commercialization and partnerships, and is also developing a graduate course in innovation and entrepreneurship.

With the lab's focus on translational research and commercialization, both Allen and Gu are excited about its potential to generate new formulations that will ultimately improve patient outcomes.

“The self-driving lab is the most cutting-edge technology to help the pharmaceutical industry to drive toward digitization, automation and ultimately improve efficiency in product development and production,” Gu says.

“With its unique capability in bridging automation and iterative discovery process, it is also the key to helping us accelerate the development and production of personalized medicines, which is prohibitively expensive and labour-intensive to be done today.”

Research challenges long-held view of early-stage Alzheimer's disease

siddiq22 — Wed, 05 Jul 2023 03:12:54 +0000

Research challenges long-held view of early-stage Alzheimer's disease

siddiq22 Tue, 07/04/2023 - 23:12

Cutline

Gerold Schmitt-Ulms, a professor in the Temerty Faculty of Medicine's department of laboratory medicine and pathology, was one of the authors of the new study (supplied image)

Eileen Hoftyzer

Topic

Breaking Research

Temerty Faculty of Medicine

Tanz Centre for Research in Neurodegenerative Diseases

Laboratory Medicine and Pathobiology

Medical Research

Research & Innovation

Subheadline

A new study by researchers from �鶹��Ƶ's Tanz Centre for Research in Neurodegenerative Diseases examines how a hormone called somatostatin influences the earliest stages of the disease

Recent research from the Tanz Centre for Research in Neurodegenerative Diseases in the University of Toronto's Temerty Faculty of Medicine is challenging long-held views of how a hormone called somatostatin influences the earliest stages of Alzheimer’s disease.

“Importantly, for the first time, this research indicates the extent to which somatostatin could be important in Alzheimer’s disease,” says Gerold Schmitt-Ulms, co-author of the study published in Scientific Reports.

“The answer is that somatostatin has a significant effect, but it’s not black or white. It doesn’t prevent clumping of the amyloid beta protein, but slows it down. This is important, but we don’t know what this means for treatment yet,” says Schmitt-Ulms, an investigator at the Tanz Centre and professor in �鶹��Ƶ’s department of laboratory medicine and pathology.

The dominant hypothesis of how Alzheimer's disease begins – the amyloid cascade hypothesis – says that too much amyloid beta protein is produced, which clumps together to form oligomers (small clumps of varying numbers of amyloid beta monomeric building blocks), which then continue to accumulate to form larger plaques that damage neurons.

As early as the 1970s, researchers observed that brains of people with Alzheimer’s disease had lower levels of the hormone somatostatin than people who did not have Alzheimer’s, and that the plaques of amyloid beta that are characteristic of the disease tend to form near neurons that produce somatostatin.

These observations suggested a relationship between somatostatin and amyloid beta aggregation, but researchers did not know what it was.

Then, in the early 2000s, a team from Japan published research describing that somatostatin drives production of an enzyme called neprilysin that can degrade amyloid beta. This finding suggested that if somatostatin was decreased, the levels of neprilysin would decrease – without neprilysin to degrade amyloid beta, the plaques would continue to grow, and Alzheimer's disease would progress.

This understanding of the role of somatostatin is where the field stood for more than a decade.

An image from the study summarizing its key findings (supplied image)

Several years ago, Schmitt-Ulms and his team investigated amyloid beta in its monomer and oligomer forms, specifically looking for molecules in the brain that would bind to the toxic oligomeric forms. They found that, of all proteins in the brain, somatostatin was the smallest to bind to amyloid beta – and the most selective, as it only interacted with the oligomers.

They then observed that somatostatin blocked the formation of oligomers, with higher concentrations of somatostatin having a greater effect. This earlier study provided the first evidence that somatostatin interacts directly with the oligomeric amyloid beta that are known to be the earliest stages of Alzheimer's disease, providing an alternative perspective on the impact of somatostatin on the disease.

“We didn’t actually intend to work on somatostatin, but these results made us very curious about what would happen if somatostatin was absent in an animal model that was genetically engineered to develop amyloid beta aggregations,” Schmitt-Ulms explains.

To answer this question, the research team crossed a somatostatin-deficient mouse line with an amyloidosis mouse model.

They found that when somatostatin was absent, there were more amyloid beta aggregates, consistent with what is seen in Alzheimer’s disease in humans.

Remarkably, the result did not seem to be caused by an effect of somatostatin on neprilysin levels, as there were no differences – a contradiction to the long-held understanding of the mechanism through which somatostatin impacts Alzheimer’s disease. Instead, the data suggested that somatostatin blocks oligomer formation independent of neprilysin by interacting with amyloid beta.

“There isn’t a lot of literature that explains how the environment in the brain can promote or inhibit amyloid beta forming into oligomers, so this is a nice vignette that shows that one molecule – somatostatin – seems to influence that first small oligomeric aggregation step,” Schmitt-Ulms says.

“And if you get fewer of these oligomeric forms, then you get fewer of the small clumps, which are the next step of amyloid beta aggregation – so the process made sense, and it was a striking finding.”

While the results have challenged the conventional view of somatostatin in Alzheimer’s and prompted discussions in the scientific community, what they mean for treatment is still uncertain.

Somatostatin plays important roles in the gastrointestinal, endocrine and nervous systems, so selectively promoting its role in blocking amyloid aggregation would be challenging. Schmitt-Ulms says that it is also unclear whether augmenting somatostatin, and thereby arresting the growth of amyloid beta aggregates, is beneficial.

Still, the results have shaken up the research field.

“The evidence speaks for itself, and we stand by our conclusions, but the data can’t answer what this means for therapeutics,” Schmitt-Ulms says.

“They do, however, indicate that somatostatin – one of the first-ever molecules that were biochemically linked to Alzheimer’s disease – may play a different role in the earliest stages of the disease than expected, and that in itself is important.”

The study was supported by Alberta Innovates Bio Solutions, Ontario Centres for Excellence/MaRS Innovation and the Borden Rosiak family.

Usage patterns amid hypertension drug recall highlight vulnerability of global supply chains: Study

Christopher.Sorensen — Fri, 14 Apr 2023 14:39:53 +0000

Usage patterns amid hypertension drug recall highlight vulnerability of global supply chains: Study

Christopher.Sorensen Fri, 04/14/2023 - 10:39

Cutline

(photo by Mint Image/Getty Images)

Eileen Hoftyzer

Topic

Breaking Research

An analysis of global usage patterns of a common hypertension drug following a major recall demonstrates the worldwide impact of contamination at a single manufacturing facility.

The research, led by researchers at the University of Toronto and published in BMJ Open, highlights the vulnerability of the global drug supply chain and the impact of drug recalls on access to safe medications, particularly in lower-income countries.

“There is very little research that has described global drug shortages or monitored how a single event can ripple around the world,” says Mina Tadrous, assistant professor in �鶹��Ƶ’s Leslie Dan Faculty of Pharmacy. “This research demonstrates that drug shortages and recalls are global and impact use around the world. And there’s evidence that they don’t affect every country in the same way.”

Valsartan, which is sold under several brand names, is a drug taken daily to treat high blood pressure and heart failure. In 2018, the European Medicines Agency detected that its supply of valsartan was contaminated by a potential carcinogen. The contamination was traced back to a single supplier of the active pharmaceutical ingredient (API), which had been manufactured in China and distributed to various manufacturers. Following the initial recall in Europe, other countries and manufacturers around the world voluntarily recalled batches of valsartan over the following few months.

Yuna Choi, a fourth-year student in the doctor of pharmacy (PharmD) program, worked with Tadrous to analyze data on the monthly purchases of antihypertensive medications in 83 countries in the period immediately before and after the recall. They aimed to determine whether purchase patterns of valsartan and other classes of hypertension drugs changed following the recall in countries of different economic status.

Their analysis showed valsartan use globally dropped significantly after the recall, but not every country changed their use in the same way. In higher-income countries, valsartan use dropped overall after the recall. Most lower-income countries, by contrast, showed similar or an overall increase in valsartan use.

Because the data in the analysis contained information about the overall consumption of valsartan in each country and did not distinguish between manufacturers or the source of API, the analysis could not offer any explanation for the differences in valsartan purchases between countries, Choi explains.

However, the finding does raise important questions about how each country managed the recall and, the study notes, “concerns of potential distribution of contaminated medications from developed countries to developing countries.”

“With globalization of the drug supply chain, disruptions can lead to global drug shortages with detrimental impacts on patient health outcomes and cause burden to the health-care system,” Choi says. “Yet, this study showed countries of different economic statuses are impacted by the recall to a differing extent.”

The analysis also provides lessons for what countries can do to protect themselves from future recalls.

“We also saw some countries did not change their purchasing patterns, perhaps by having a diverse supply chain or being protected in some other way. There might be an opportunity to learn from other countries that weren’t as affected by the recall,” Tadrous says. “Every country seems to be tackling this problem on their own, and there needs to be a concerted effort to work together to protect supply chains.”

The global drop in valsartan use following the recall also highlights the vulnerability of the drug supply chain to shortages from even just one local problem and gaps in accessing safe medications.

“Contamination in one local facility led to a global impact that affected millions of patients who take this medication every day,” Choi says. “If pharmaceutical manufacturers are relying on the same source of API as other manufacturers, how can we claim that we have options and good backup supplies in the case of a recall?

“These shortages and recalls can have significant consequences on clinical outcomes and health system costs, but they can be prevented through policy and strategy to address the underlying causes and mitigate their effects globally.”

Pandemic highlighted drug shortages and supply-chain issues

Choi has been interested in examining the impact of pharmacy policy and regulations since starting the PharmD program. Undertaking the research project with Tadrous allowed her to explore a different side of the profession. As she nears the end of the program, she says she will be pursuing a master’s degree in pharmaceutical science at the Leslie Dan Faculty of Pharmacy to continue examining issues related to access to safe medications.

She hopes that the research on the valsartan recall will raise more awareness of the disproportionate impact of drug shortages on lower-income countries and the need for a global effort to improve access to medications – an issue that became more common during the COVID-19 pandemic.

“Drug shortages are not a new problem, but COVID-19 has certainly shed light on these drug shortages,” Choi says. “It’s important that there is a global effort to ensure that patients worldwide have access to medication – and that countries work together to ensure that medication supplies are safe.”

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