September 24, 2020

Clinical study simplifies precision medicine for pancreatic cancer patients

Liver biopsy image from a patient with metastatic pancreatic ductal adenocarcinoma. Dual immunohistochemistry reveals expression of GATA6 (brown) or CK5 (magenta) in distinct cells within the same neoplastic glands. (Credit: Clinical Cancer Research)

OICR-supported researchers discover new way to match advanced pancreatic cancer patients with the most appropriate treatment for their disease

Over the next 10 years, it is expected that pancreatic ductal adenocarcinoma (PDAC) will become the second leading cause of cancer-related deaths in North America. Precision medicine for PDAC is dependent on understanding which cancers will respond to treatment and which will not, but progress in this space has been limited by challenges including the complexity and severity of the disease. With more than 10 years of clinical and genomic data from the COMPASS trial, OICR-supported researchers have recently discovered a new, simplified way to match patients with the most appropriate treatment for their disease by measuring the expression of two genes, GATA6 and Keratin 5. Their discovery was recently published in Clinical Cancer Research.

Dr. Grainne O’Kane

“Even with current chemotherapies, patients diagnosed with PDAC have a median survival of one year,” says first author Dr. Grainne O’Kane, Medical Oncologist at the Princess Margaret Cancer Centre. “This work is dedicated to extending the lives of these individuals.”

The study group discovered that by measuring the expression of GATA6 and Keratin 5 in a patient’s tumour sample, they can differentiate subtypes of advanced pancreatic cancer. The different subtypes of the disease tend to respond to treatments differently, so clinicians and patients could potentially use this information to help guide treatment selection.

More specifically, the group showed cancers with low GATA6 expression and high Keratin 5 expression tend to be resistant to mFFX, one of the usual chemotherapy regimens. The study highlights the need for new, effective treatments for these patients.

Dr. Sandra Fischer

“To discover these specific genes, we used sophisticated sequencing and in-depth analyses, but what we’ve found is that this classification can be done using simpler, widespread pathology techniques,” says senior author Dr. Sandra Fischer, Staff Pathologist at University Health Network. “This is promising because these discoveries can be easily applied in the clinic, and translated into patient care.”

The article was selected by Clinical Cancer Research to be highlighted on the front cover of the September 2020 issue and featured as one of the Issue Highlights.

Through the COMPASS trial, the researchers plan to further evaluate and validate this classification technique.

“I’m proud to be part of this team,” says Fischer. “Every step we take is a stride forward towards more precision and effective treatment for patients with this devastating disease.”

In December 2015, PanCuRx launched a clinical trial called Comprehensive Molecular Characterization of Advanced Ductal Pancreas Adenocarcinoma for Better Treatment Selection: A Prospective Study (COMPASS). The trial is designed to show that the sequencing of pancreatic tumours can be performed in a clinical setting and results delivered within a clinically-relevant timeframe to help guide treatment for individual patients. Read more on the latest COMPASS findings.

September 16, 2020

CanPath adds Saskatchewan cohort, all 10 provinces now represented

This post was edited and republished with the permission of CanPath.

CanPath is pleased to announce that, with funding support from the Canadian Partnership Against Cancer, a Saskatchewan cohort will be developed and join the CanPath study. The Saskatchewan Partnership for Tomorrow’s Health (Saskatchewan PATH) will add approximately 9,000 participants to the existing cohort of over 330,000 Canadian participants. The addition of Saskatchewan means that all 10 Canadian provinces have now joined CanPath.

Saskatchewan PATH will create a platform and resource for fostering research in cancer and chronic disease prevention within the province. The Saskatchewan PATH study will be led by Scientific Director, Riaz Alvi and hosted by the Saskatchewan Cancer Agency.

“We are excited to officially welcome Mr. Alvi and the Saskatchewan PATH team to the CanPath partnership. We look forward to working together to develop a truly pan-Canadian study and sharing learnings from our other regional cohorts to support Saskatchewan PATH as they move forward,” says John McLaughlin, Executive Director of CanPath.

 “We are proud to be a part of this truly national program.  Saskatchewan holds a prominent place in the history of healthcare in Canada, and houses one of the world’s oldest cancer registries.  We are confident that the people of Saskatchewan will welcome this opportunity to participate in Saskatchewan PATH to help further a better understanding of cancer and other chronic diseases, and to assist with the future development of prevention, early detection, diagnosis and treatment programs.  There is exciting and highly rewarding work ahead of us.” says Riaz Alvi, Scientific Director of Saskatchewan PATH.

Saskatchewan has a unique and diverse population, with roughly half living in the province’s largest city, Saskatoon, or the provincial capital of Regina. The province’s economy is primarily associated with agriculture and more recently mining. The burden of cancer in Saskatchewan is significant with about 5,600 new cancers diagnosed in 2018 and just over 2,000 cancer deaths in the same year. In 2018, the number of people living with cancer that had been diagnosed within the last 5 years (5-year prevalence), was approximately 17,000 people.

“Since CanPath began almost 11 years ago, we have sought to ensure representation of all provinces. Now being able to include participants from the province of Saskatchewan fills an important gap, and builds upon the hard work of many of us who started and have maintained the CanPath cohort and vision since the beginning,” says Philip Awadalla, National Scientific Director for CanPath.

With CanPath’s guidance and support of the development of Saskatchewan PATH, the new cohort will benefit from the experience and lessons learned by CanPath’s other regional cohorts. Saskatchewan PATH joins the six regional cohorts that currently makeup CanPath: BC Generations Project, Alberta’s Tomorrow Project, Manitoba Tomorrow Project, Ontario Health Study, CARTaGENE (Quebec), and Atlantic PATH.

The development of Saskatchewan PATH will consist of three phases:

  • Phase I – Planning & Implementation (Present to March 2022)
  • Phase II – Participant Recruitment and Collection of Data and Biological Samples
  • Phase III – Maintenance and Use of Participant Data and Biological Samples

About CanPath

The Canadian Partnership for Tomorrow’s Health (CanPath) is Canada’s largest population health cohort and a national platform for health research. Comprised of more than 330,000 volunteer participants, CanPath is a unique platform that allows scientists to explore how genetics, environment, lifestyle and behaviour interact and contribute to the development of cancer and other chronic diseases. CanPath is hosted by the University of Toronto’s Dalla Lana School of Public Health with national funding from the Canadian Partnership Against Cancer. The Ontario Institute for Cancer Research (OICR) hosts CanPath data in a safe and secure environment. To learn more, visit www.canpath.ca.

The original post can be viewed here: https://canpath.ca/2020/09/canpath-completes-provincial-map-with-addition-of-a-saskatchewan-cohort/

August 31, 2020

Research from home: Kelly McDonald

Learn about the research that the Ontario Health Study has been doing during COVID-19 and how scientists have managed to do this work from home.

August 28, 2020

The tools behind the treatment: Building image-guided devices for more accurate and effective cancer procedures

OICR-supported researchers develop multi-purpose AI algorithm to help track needle placement and improve the accuracy of several image-guided treatment techniques

Dr. Derek Gillies and Jessica Rogers
Dr. Derek Gillies and Jessica Rodgers

Cancer patients often encounter many needles, some of which are used to collect tissue samples or deliver therapy directly to a tumour. Specialists who carry out these procedures are trained to place needles precisely in the correct location, but what if we could give these specialists a real-time GPS for needles? Would biopsies be more accurate? Could needle-related therapies be more effective?

Dr. Aaron Fenster’s lab is working to develop tools for these specialists to guide their needles and ultimately improve the accuracy of biopsies and therapies for patients. In their recent paper, published in Medical Physics, they describe their new deep learning method to track needles in ultrasound images in real time.

“It may be surprising to many individuals, but a lot of these procedures are still done based on skill alone and without image processing,” says Dr. Derek Gillies, medical physicist in training and co-first author of the paper. “We’re working to provide clinicians with tools so they can better see their needles in real time rather than going in blind for some procedures.”

The deep learning methods presented in this paper are applicable to many types of needle procedures, from biopsies – where a clinician draws a tumour sample from the body – to brachytherapy – where a clinician delivers radiotherapy directly to the tumour. The methods could also be applied to several cancer types including kidney cancer, liver cancer and gynecologic cancers.

“Developing artificial intelligence algorithms requires a lot of data,” says Jessica Rodgers, co-first author of the paper and PhD Candidate at Western University’s Robarts Research Institute. “We didn’t have a lot of imaging data from gynecologic procedures, so we decided to team up to develop a method that could work across several applications and areas of the body.”

“That’s the most exciting aspect of this effort,” says Gillies. “To our knowledge, we were the first to develop a generalizable needle segmentation deep learning method.”

Now, members of the Fenster lab are working to integrate these algorithms into the video software equipment used in the clinic.

“Our work is giving clinicians new tools, which can help them make these procedures more precise and more accessible,” says Rodgers. “These tools could ultimately help lead to fewer missed cancer diagnoses and fewer patients with cancer recurrence.”

Read more about OICR’s Imaging Program, or the latest OICR Imaging news.

July 23, 2020

Prevention before treatment: How an OICR investigator is shifting the paradigm of chronic disease in Canada

The BETTER Program for chronic disease prevention and screening now customized for young adults, women and cancer survivors across the country

Dr. Eva Grunfeld

Cancer doctors are extensively trained to find and treat the disease, but what about preventing cancer in the first place?

Dr. Eva Grunfeld is dedicated to making prevention a priority.

In 2012, Grunfeld established the BETTER Program and today, this Canada-wide initiative is expanding and adapting to serve more individuals across the country.

Since its inception, BETTER has trained nearly 250 health professionals to become Prevention Practitioners who specialize in chronic disease prevention and screening. These Prevention Practitioners work in the primary care setting to develop personalized “prevention prescriptions” that are tailored to each patient based on an in-depth analysis of their medical history, family history, lifestyle factors, and other risk factors for diabetes, cardiovascular disease and cancer.

Continue reading – Prevention before treatment: How an OICR investigator is shifting the paradigm of chronic disease in Canada

June 17, 2020

Inside OICR’s Drug Discovery Lab: A graduate student’s unique collaborative experience

An open-science brain cancer drug development initiative makes for a memorable master’s experience

Deeba Ensan

Diffuse intrinsic pontine glioma (DIPG) is a complex, lethal and inoperable type of childhood brain cancer with a median survival of less than a year from diagnosis. Not only is DIPG difficult to treat, it is also extremely rare, making it a particularly challenging disease to study. Given this challenge, those studying DIPG have come together from around the world to find new solutions together.

When University of Toronto master’s student Deeba Ensan heard that OICR was contributing to DIPG research, she was eager to help. Over the last two years, Ensan has made considerable progress towards a new drug for DIPG.

Continue reading – Inside OICR’s Drug Discovery Lab: A graduate student’s unique collaborative experience

June 2, 2020

Q&A with new OICR investigator Dr. Hartland Jackson on the latest in mass cytometry, single-cell imaging and his return to Canada

Dr. Hartland Jackson.

OICR welcomes Dr. Hartland Jackson back to Toronto as Lunenfeld-Tanenbaum Research Institute and OICR’s newest investigator

While he was a doctoral student developing experimental models of breast cancer, Dr. Hartland Jackson recognized the enormous potential impact of multiplexed imaging and single-cell technologies. If we could see how different cells interact within a tumour, what could we discover?

This question fueled his research over the last half decade, taking him to Switzerland to develop advanced imaging methods alongside experts at the University of Zurich. Now, returning to Canada, Dr. Jackson plans to collaborate across disciplines and sectors to apply this technology to solve more scientific and clinical questions. Here, he discusses his goal of bringing the benefits of this technology to more patients in Ontario and around the world.

What was your main research focus in Switzerland?

HJ: In a nutshell, I was developing a new technology, called imaging mass cytometry, which allows us to visualize and analyze tumour samples in more detail than ever before.

When I joined the research group at the University of Zurich, they had developed a prototype imaging system. My role was to take this system and be the first to apply it to a clinical problem. Ultimately, I helped shepherd the system from a prototype to a commercial product that is now used around the world.

What clinical application did you focus on?

HJ: I focused on investigating how this technology could help in the diagnosis and prognosis of breast cancer. Through this process, we made a lot of progress in developing analysis methods and optimizing the system. Whereas traditional imaging methods could see three or four markers on a cell, our system allows us to see 40 markers at the same time. With this technology and imaging system, we could visualize how different cells were organized within a sample, which revealed new types of breast cancer.

In addition to this discovery, my work showed that imaging mass cytometry can reveal information within clinical samples – meaning information that may be useful for patients. We pushed the boundary on what can be done with this system and now it’s used around the world to study different human diseases.

Interestingly, the technology that I was working on was an adaptation of an earlier technology developed in Toronto by DVS Sciences, which was supported in part by OICR. My plan was to work with the imaging experts in Switzerland and bring these developments back to the place where the technology was created and is now manufactured as a commercial product by Fluidigm.

Is that what brought you back to Canada?

HJ: Yes, one of the reasons I’ve returned to Canada is to bring this expertise back to Toronto. In addition to that, the research community here is very impressive. The universities, research institutes and hospitals are all tightly knit. This makes for an excellent environment to develop new technologies that can address clinical health challenges. I find that researchers here are like-minded in their goals and collaborative spirit. We enjoy working through technical challenges and delving into the mysteries of cell biology, and – at the same time – working on research that really matters to patients.

What will your future research focus on?

HJ: I plan to continue developing some of the methods that I was working on in Europe while expanding my research in a few exciting areas.

We’re looking to apply this technology to different types of cancer and different diseases in collaboration with clinician scientists. I’m interested in applying this technology in drug clinical trials to help us understand how patients respond to different therapies. In parallel, I look forward to using this technology to study experimental model systems to better understand how cells are communicating with each other and what goes wrong in the communication between cells during cancer development.

Our work has shown what this technology is able to do and that has only opened more avenues for future research. I’m excited because these new applications are now within our reach. To date, collaborations have allowed me to make more progress than I could have ever made on my own and I look forward to building new collaborations to make new discoveries in the future.

Visit Dr. Hartland Jackson’s OICR website page

May 20, 2020

Study points to common protein duo as a new therapeutic target for several cancer types

Structure of the RUVBL1 protein. (Credit: Emw / CC BY-SA (https://creativecommons.org/licenses/by-sa/3.0))

Local research group discovers a new way to shut down a pair of cancer-driving proteins, pontin and reptin, using the structure of an FDA-approved drug

Pontin and reptin are proteins that are involved in several cancer-driving mechanisms and play key roles in several diseases, including liver, colorectal, breast, lung and bladder cancers. This makes them a hot target for cancer drug development and discovery efforts. Currently, there is only one drug class that may hold some promise to shut down these proteins, but a Toronto-based team of scientists has recently broken new ground.

Dr. Walid Houry’s Lab at the University of Toronto and OICR’s Drug Discovery group have discovered that pontin and reptin, also known as RUVBL1 and RUVBL2, may be blocked to prevent cancer growth using a chemical similar to the FDA-approved drug, sorafenib. Their findings, which were recently published in Biomolecules, could be a starting point for new and improved cancer drugs based on the approved drug’s structure and function.

Dr. Nardin Nano.

“Through our research, we detangled a large, complex process of interactions between proteins, but what we found was both rewarding and exciting,” says first author Dr. Nardin Nano, who was a PhD student in the Houry Lab while leading the study. “Our findings suggest a new target for cancer treatment and that a new therapy could be within reach.”

This study is part of a larger initiative, led by Nano and members of the Houry Lab, to further describe the function of these proteins in helping cancers grow and invade tissues. With their newfound understanding, the Houry Lab will continue to design and develop molecules similar to sorafenib that can better target pontin and reptin.

“I look forward to future studies that will use this knowledge to better inhibit these proteins in vivo,” says Nano. “Although there is more work to be done, I’m proud that this discovery can help guide future drug development efforts.”

“Given the multiple roles of pontin and reptin in carcinogenesis, it’s not surprising that they are promising drug targets,” says Houry, who is a Professor at the University of Toronto and supported by OICR’s Cancer Therapeutics Innovation Pipeline. “These findings motivate us to continue developing pontin and reptin inhibitors as potential anti-cancer compounds that could – one day – help a number of patients with the disease.”

May 6, 2020

A message from OICR’s President and Scientific Director, Dr. Laszlo Radvanyi

Dr. Laszlo Radvanyi

I hope that everyone has continued to stay safe and healthy as the world continues to grapple with the risks and challenges presented by COVID-19. The impacts of the pandemic have been felt by individuals and organizations across society, including cancer patients and Ontario’s cancer research community.

While things are obviously not business as usual, I am happy to see OICR’s people rise to the challenge and find solutions to allow us to continue to focus on cancer research while working remotely. My thanks go to OICR’s staff, Board and Scientific Advisory Boards, collaborators and others who have quickly adapted to continue our work as best we can. A big thank you also to our funders at the Ministry of Colleges and Universities for their continued support. We will gradually restore our onsite cancer research activities in a manner that will ensure a safe work environment for all our onsite staff. Our priority remains to improve the lives of those with cancer through research.

OICR’s leadership recognizes that the pandemic has resulted in unprecedented challenges for cancer researchers across Ontario. We have taken steps to ease this burden and are working with OICR-funded researchers and partner organizations to overcome these challenges together. More information about how we are assisting our funded researchers can be found on our website.

Due to our collaborative, cross-disciplinary research strengths, OICR is well-situated to contribute to COVID-19 research. OICR researchers are engaged in numerous projects with others in Ontario and abroad. It has been heartening to see such a swell of collaborative spirit and to see the research community doing what we can to help overcome COVID-19. I invite you to visit our website to learn more about how OICR is doing its part. We are especially cognizant on how these research activities impact cancer patients, as they are an especially vulnerable population at this time.

COVID-19 has disrupted cancer research on a global scale. I look forward to a time when we can resume all of our research activities and once again contribute to the international campaign against cancer at full capacity. During the pandemic, cancer has not and will not cease to be a reality for the thousands of Ontarians living with this disease and their families. Everyone at OICR remains steadfast in our commitment to improve the lives of those facing cancer.

In closing, I offer my deepest appreciation to all those working on the front lines of this crisis and thank all off the members of Ontario’s cancer research community for their continued dedication during this difficult time. All our thoughts also go out to any families that have been affected during this crisis.

Sincerely,
Dr. Laszlo Radvanyi
President and Scientific Director
OICR

April 1, 2020

Measure up: Taking strides to automate cancer pathology practices

Dr. Tamara Jamaspishvili

OICR-supported researchers quantify common prostate cancer outcome predictor

Advances in cancer research have opened the door to new tests to better assess tumours and help recommend the most appropriate course of treatment for a patient. Research pathologists play a critical role in turning scientific knowledge into tests that can be used in an everyday clinical setting.  

“Scientists are constantly advancing our understanding of cancer, but that understanding cannot help patients unless it’s applied in practice,” says Dr. Tamara Jamaspishvili, Research Pathologist at Queen’s Cancer Research Institute. “Our role as research pathologists is to bridge that gap, and transform discoveries into more accurate diagnoses and prognoses for patients that could be implemented and actionable in practice.” Jamaspishvili’s work is supported by the Ontario Molecular Pathology Research Network, an OICR-funded province-wide network that conducts high-quality cancer research focussed on clinical impact.

An example of the challenge of clinical translation is found in PTEN testing. PTEN is a cancer-preventing gene that – when absent in a cell – may lead to uncontrolled tumour growth. Research has shown that the loss of PTEN within a prostate tumour could help predict the severity of a man’s prostate cancer, but PTEN is not routinely tested.

“Simply put, some cells in a tumour sample may have PTEN loss and some cells don’t, but nobody has clearly quantified how the ratio of cells with or without PTEN contribute to a patient’s health,” says Jamaspishvili.

Jamaspishvili teamed up with collaborators to address the subjectivity of PTEN testing. Her collaborators include Drs. David Berman, Palak Patel, Robert Siemens, Paul Peng, and Yi Niu from Queen’s Cancer Research Institute, Drs. Fred Saad and Anne-Marie Mes-Masson from the University of Montreal, Dr. Tamara Lotan from Johns Hopkins University, and Dr. Jeremy Squire and colleagues at the  University of São Paulo.

Their study, recently published in the Journal of the National Cancer Institute, proposes a new quantitative approach to assess PTEN. They clarify how pathologists can predict the severity of a patient’s prostate cancer based on the number of cells with PTEN loss. These findings can help standardize PTEN testing, but their approach can also be applied to other pathology tests that are still highly subjective.

“Quantifying qualitative tests helps us move towards automated pathology techniques,” says Jamaspishvili. “This is the future of pathology.”

Jamaspishvili is now working to automate PTEN digital pathology analysis in collaboration with Dr. Stephanie Harmon and colleagues in Dr. Baris Turkbey’s lab as part of the National Cancer Institute’s Molecular Imaging Program.

“Now, we can apply machine learning image analysis tools to analyze PTEN loss and make better predictions for the benefit of patients. We look forward to using artificial intelligence in digital pathology to help fill the gaps between research and clinical practice.”

Read more about OMPRN.

March 12, 2020

The complexities of head and neck cancers may be simpler than we thought

Drs. Sampath Loganathan and Daniel Schramek.

Toronto-based research team uncovers dozens of rare mutations found in head and neck cancers converge on a single molecular pathway, amplifying the need to shut down this critical cancer-causing mechanism

With the advancement of DNA sequencing technology, researchers have discovered hundreds of genes that, when mutated, can drive cancer progression. Despite these discoveries, we don’t yet fully understand how the majority of cancer-causing genes work, leaving a large gap between the discovery of a gene mutation and the discovery of a new therapy. Dr. Daniel Schramek is filling that gap.

In a recent study, published in Science, Schramek and collaborators, including Dr. Trevor Pugh, Director of Genomics at OICR, analyzed the function of nearly 500 gene mutations found in head and neck cancers. Remarkably, they discovered that the many of these mutations affected one key molecular process within cancer cells. They shut down NOTCH signaling.

“While we see many different mutations in different genes across different patients, we found that many mutations, surprisingly, tend to do the same thing,” says Schramek, who is an investigator at Sinai Health’s Lunenfeld-Tanenbaum Research Institute (LTRI). “This means the complexities of head and neck cancers may be simpler than we thought”

Schramek reasons that focusing on correcting the NOTCH pathway, rather than correcting the effects of each individual gene mutation, could simplify and focus the search for new and improved cancer therapies. He estimates that approximately 70 per cent of people with head and neck cancers have tumours that are affected by this pathway. Thus, a large majority of these patients could benefit from NOTCH-correcting cancer drugs.

“Every patient’s tumour is made up of different gene mutations and combinations of these mutations,” says Dr. Sampath Loganathan, first author of the study and Postdoctoral Fellow in the Schramek Lab. “Some of the more common, well-understood mutations are druggable – meaning they can be blocked with drugs – but there are hundreds of rarer, but important, mutations that we don’t yet understand.”

It is challenging to understand how a single mutation causes damage within a cell and ultimately leads to cancer. It is tremendously more challenging to understand the function of hundreds of mutations.


Our findings present a new way of thinking about precision oncology

Dr. Daniel Schramek

Schramek’s lab, however, developed an experimental system that allowed them to accelerate traditional functional testing for a fraction of the cost. Their system could test hundreds of gene mutations in a single mouse model. What would take several millions and decades in research and development, could now be done in one year for a fraction of the cost. Equipped with their powerful tools, this research group was the first to systematically look at rare mutations in head and neck cancers.

Schramek and collaborators are now working to identify key elements within the NOTCH pathway that can be blocked with chemicals. Their ultimate goal is to develop these chemicals into new drugs to help those with head, neck and other types of cancers. They will also continue to explore this phenomenon in other cancers such as breast and pancreatic cancers.

“Our findings present a new way of thinking about precision oncology,” Schramek says. “Instead of matching patients with specific mutations to specific treatments, researchers could focus on shutting down or restoring the pathways involved with those genes – hence, a pathway-centric model of precision oncology. We’re excited by this progress, and we look forward to bringing our ideas to future patients.”

This research was done in collaboration with OICR and was supported by the Canadian Institutes of Health Research, the Terry Fox Research Institute and the Human Frontier of Science Program. Schramek is a Kierans/Janigan Cancer Research Scientist and holds a Canada Research Chair in functional cancer genomics in the Department of Molecular Genetics at the University of Toronto.

Read more about this work in the Lunenfeld-Tanenbaum Research Institute’s news story.

February 27, 2020

Innovative drug screening method finds new promising molecules to treat aggressive lung cancers

Igor and Rima
Dr. Igor Stagljar (Photo by Sam Motala) | Dr. Rima Al-awar

International research group finds leukemia drugs and other small molecules may shrink treatment-resistant lung tumours

Lung cancer is the leading cause of cancer death in Canada and around the world. These fatal cancers often arise as a patient’s tumour cells acquire new mutations and become resistant to treatment but Dr. Igor Stagljar has found a new way to stop these tumours. In fact, he may have found four.

Stagljar’s research group at the University of Toronto is well-known for developing a live drug screening method – named MaMTH-DS – that can test potential cancer-fighting molecules in living cells. In a recent study published in Nature Chemical Biology, he and collaborators used these methods to focus on a common mutation, dubbed C797S, which often arises in lung cancers just months after initial treatment. The group identified four new compounds that could block the effects of C797S mutations with no effect on healthy cells.

“Our new technology allows us to find molecules that could be used against cancers for which no other treatment options are available,” says Stagljar, who is a professor of molecular genetics and biochemistry at the University of Toronto. “The advantage of our method is that we are doing it in living cells, where we have all the other molecular machineries present that are important for signal transduction. Also, the compounds are fished at very low dose, which allows us to test for both permeability and toxicity at the same time.”

Conventional drug screening strategies were not able to detect these compounds but Dr. Stagljar’s approach brought these new promising molecules to light.

Dr. Rima Al-awar

Two of the molecules identified have already been approved for patients with leukemia. Motivated by their recent findings, Stagljar and collaborators plan to evaluate the effects of these compounds in patients with lung cancer. The first clinical trial to evaluate one of these drugs – gilteritinib – is expected to launch later this year in Toronto, Canada and Zagreb, Croatia.

The other two molecules will require further research and development before they can be trialed in patients. One of these molecules, known as EMI1, could shut down the mutated cells in a completely new way, leveraging molecular machineries to degrade mutated proteins on the surface of tumour cells. The researchers think that EM1’s complex mechanism of action will make it more difficult for tumours to develop resistance to it.

Stagljar is working with Dr. Rima Al-awar, Head of Therapeutic Innovation and Drug Discovery at OICR, and her medicinal chemistry team to create an improved version of the EMI1 molecule. If proven successful, this molecule could potentially become a new treatment for the estimated 60,000 lung cancer patients worldwide who have the C797S mutation.

“Dr. Stagljar’s novel screening approach has identified these very promising molecules” says Al-awar. “We’re proud to collaborate with him and his group to further advance these molecules and accelerate the stages of experimentation between his discovery and helping those with the disease.”

Al-awar, whose drug discovery team recently brought a molecule for blood cancers into pre-clinical development, will leverage her group’s expertise to refine the molecule and move it into the next stage of development, where its ability to shrink tumours can be evaluated in experimental animal models and eventually patients.

This research was supported in part by the Consortium Québécois sur la Découverte du Médicament (CQDM), Cancer Research Society (CRS), Canadian Institute of Health Research (CIHR), Genome Canada and Ontario Research Fund. Stagljar was recently awarded a Prospects Oncology Fund grant from FACIT, OICR’s partner in commercialization, to develop a related drug screening platform, SIMPL.


This post has been adapted from the original announcement made by the University of Toronto Donnelly Centre.

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