February 27, 2020
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.
November 1, 2019
Al-awar joins OICR’s executive team with plans to expand drug discovery and development initiatives across Ontario
Dr. Rima Al-awar has joined OICR’s executive team as Head, Therapeutic Innovation and Drug Discovery. In this role, she will lead one of OICR’s three key priority areas, Therapeutic Innovation, which focuses on validating novel cancer drug targets and advancing therapeutic candidates through pre-clinical development. She will continue leading OICR’s Drug Discovery Program and will build upon that team’s exceptional work in her new position.
Here she discusses her new role and her plans to grow OICR’s Therapeutic Innovation platform.
What does this promotion mean for you and your team?
Since joining OICR, I have spent several years building an experienced and talented team that I’m very proud of. We have developed great assets and established fruitful partnerships with collaborators and industry partners. We have a very rich and promising portfolio of potential new cancer therapeutics.
I believe we are in a great position to expand and capitalize on our successes. My new position will allow me to take a strategic role in therapeutic innovation at OICR so that we can enable future successes both here, in Toronto, and across the province. I need to think of creative and strategic funding models, how best to strengthen the platform’s structure and establish additional synergistic partnerships in the community. In the long run, this means advancing more projects into development.
How will this new role allow you to do that?
I’ll have a seat at the table in strategic conversations with our executive team. I’ll bring a unique perspective with my expertise in drug discovery and development, and I look forward to representing Therapeutic Innovation, an important part of OICR.
In this role I will also help ensure that resources are allocated to the most promising projects. I’m a big proponent of focusing on select projects and doing them well and in a timely and competitive fashion as opposed to stretching our resources across too many projects, which often ends up slowing progress. In this position, I believe I can do that more effectively.
How does this new appointment differ from your previous position as Director of Drug Discovery?
I will still be leading the Drug Discovery team, but I’ll be relying on leaders within the team to take on some of my previous day-to-day responsibilities, and in turn, they will delegate some of their current responsibilities. I see this role as an opportunity to strengthen the Drug Discovery team and encourage the pace of career development within the team.
Within the scope of my new role, we are going to have to think creatively about progressing additional projects forward faster, which will mean harnessing new technologies and recruiting new expertise in different scientific disciplines.
When it comes to collaborations, I expect that my role will be just as collaborative as it was before. My goal is to continue to strengthen our current collaborations and forge new ones. We can’t bring new therapeutics to patients on our own.
What can we expect to see over the next year?
I want to explore the idea of expanding our breadth of collaborations to include biologics, immunotherapies, and novel drug delivery methods, technologies and models that impact drug discovery. I will be travelling to different research institutes across the province and outside of Ontario to look for more opportunities. The goal of this effort would be to identify and build on strengths in the community. We’re looking to enable and facilitate new, promising projects in areas of unmet needs. Expanding our network across Ontario is very important. We have built a strong foundation, we have deep expertise, a rich portfolio and now we are going to take it to the next level. I look forward to encouraging more synergy across our organization and Ontario.
March 8, 2019
OICR’s Drug Discovery team and Princess Margaret Cancer Centre researchers collaborate to turn a research discovery into a potential cancer breakthrough
For more than three decades, researchers have tried to develop drugs that target the MYC oncoprotein – a protein that can contribute to half of all cancers – but traditional approaches to blocking MYC have not been successful. The structure of the MYC protein makes it ‘undruggable’; it cannot be blocked by a small molecule or a drug, so new strategies to inhibit the activity of this protein are needed.
Dr. Linda Penn, Senior Scientist at the Princess Margaret Cancer Centre, recently discovered a new way of preventing MYC from promoting cancer growth by stopping the interaction between the MYC protein and a ‘druggable’ partner protein, G9a.
“We investigated MYC and discovered G9a as a key partner protein. We blocked G9a using both genetic and pharmacological strategies. We saw that inhibiting G9a using an inducible knockdown strategy had the potential to melt tumour cells away,” says Penn. “But for some reason, no matter what we tried, we didn’t see the tumour-fighting effect of the G9a compound inhibitor in animal models. Something didn’t line up.”
A discovery like Penn’s, however, can only be brought to patients if it can first be demonstrated in living experimental models, also known as in vivo. The results of Penn’s in vivo experiments were inconclusive, preventing her from publishing her promising findings in a top-tier journal and advancing this line of research.
Navigating the preclinical minefield
The compound – or molecule – that Penn’s team was using to block G9a in vitro wasn’t doing the same in vivo and they didn’t understand why. Lacking the medicinal chemistry expertise needed to solve this problem, Penn turned to OICR’s Drug Discovery group.
“All of Dr. Penn’s experiments and all of the published literature implies that the compound should have worked, but unfortunately that wasn’t her observation,” says Dr. Ahmed Aman, Principal Research Scientist in the Drug Discovery group at OICR. “We had to break this problem down and solve it methodically while considering the various factors that could have contributed to these results.”
The Drug Discovery team evaluated the compound and found that it didn’t have the drug-like properties necessary to demonstrate activity in vivo. More specifically, they discovered that the compound would break down in the body before having a chance to inhibit G9a. Although the compound that they tested would not be useable as a drug, Penn’s study was now conclusive. Finding the missing piece of the puzzle allowed her team to publish their discovery in Cancer Cell and proceed with identifying and investigating new compounds to target G9a more effectively.
Collaboration to translation
Penn says that she worked with the Drug Discovery group because of their stellar reputation in the industry, strong track record and unique expertise.
“Without the Drug Discovery team, I really don’t know where I would have gone,” says Penn. “I simply didn’t have established relationships with medicinal and analytical chemists nor private industry to help me solve these chemistry problems.”
Together, Penn and the Drug Discovery group are continuing to investigate G9a and how to block it from interacting with the MYC protein. They are using another reported G9a inhibitor, which has been prepared in-house by the Drug Discovery team that Aman says should be able to work much more effectively in vivo.
“Our collaboration with the Penn group is a great example of how we hope to leverage our drug discovery capabilities to support investigators across Ontario and advance their research efforts,” says Dr. Rima Al-awar, Director and Senior Principal Investigator of OICR’s Drug Discovery group.
Learn more about OICR’s Drug Discovery services and capabilities through the Collaborative Research Resources directory.
February 7, 2019
Op-ed in The Globe and Mail hails innovation strategy that resulted in record-breaking investment by Celgene
In a contribution to The Globe and Mail titled “For Innovation, open science means business”, E. Richard Gold and Max Morgan point to the recent investment by U.S. pharmaceutical giant Celgene into a potential treatment for leukemia developed by OICR researchers, as an example of how Canada can successfully commercialize its scientific discoveries. The authors note that the uniquely Canadian approach employed by FACIT and OICR working together will, unlike other strategies, keep the intellectual property (IP) in Canada longer and see research and development, clinical trials and other outcomes, benefit Canada and Ontario.
Gold and Morgan point out that it was an open science collaboration between OICR and the University of Toronto’s Structural Genomics Consortium (SGC) that allowed for the initial scientific discovery behind the new potential drug to take place rapidly, since traditional concerns around IP weren’t a factor. This approach allowed FACIT and OICR to move towards targeted drug development much earlier than possible under other models, enabling them to create a patented drug candidate. Gold and Morgan call on Canadian governments to replicate the open science to IP model, which Celgene’s investment shows is a viable path to commercialization in Canada.
E. Richard Gold is James McGill professor, McGill Faculty of Law; senior fellow, Centre for International Governance Innovation; former technology lawyer. Max Morgan is chief policy officer and senior counsel, SGC; corporate secretary and legal consultant, M4K Pharma Inc. OICR has provided funding to M4K Pharma Inc. through its Cancer Therapeutics Innovation Pipeline initiative. SGC and OICR are long-term partners.
From the Globe and Mail (subscription required): For Innovation, open science means business
February 14, 2018
At OICR and FACIT, women play a vital role in both ground-breaking cancer research and leading innovations from the lab to the marketplace – benefitting patients and the Ontario economy. In the first part of this two part series, female executives, leaders, directors, and scientists from OICR and FACIT shared their perspectives on challenges facing women in science. Now they discuss what can be done to address these challenges.
Despite the advances made in recent years, achieving equality and parity in science remains a significant challenge for policy-makers, organizations and the scientific community at large. We spoke with a panel of women from OICR and FACIT about the approaches to parity in science, discussing strategies and changes to better represent and support women.
February 12, 2018
At OICR and FACIT, women play a vital role in both ground-breaking cancer research and leading innovations from the lab to the marketplace – benefitting patients and the Ontario economy. These women also acknowledge the challenges and barriers for women within the field of science. The International Day of Women and Girls in Science, on February 11, calls for greater commitment to end bias, increased investment in STEM for all women and girls and opportunities for their long-term professional advancement. In the first part of this two-part story, female executives, leaders, directors, and scientists from OICR and FACIT share their perspectives on the challenges faced by women in science.
May 1, 2016
OICR is supporting new early stage drug discovery research in Ontario, with a $1.2 million investment from OICR’s Drug Discovery Program into five promising oncology research projects selected through a province-wide call for proposals.
This was a new approach to selecting projects for the Drug Discovery team’s research pipeline and one that aligns well with the strategic direction of the team and the Institute, says Dr. Rima Al-awar, Director of OICR’s Drug Discovery Program.
“Traditionally we have relied on several means to generate interest from the community, including informal outreach to other institutions and word of mouth says Al-awar. She points to the recent success of BCL6, a drug target that OICR’s Drug Discovery team developed from early stage research by Dr. Gil Privé at University Health Network. Collaborating with Privé, the team brought the BCL6 project to the point where it attracted major investment from industry.
September 3, 2015
The Ontario Institute for Cancer Research and the Structural Genomics Consortium develop and give away new drug-like molecule to help crowd-source cancer research
Through a novel open source approach the molecule has been made freely available to the cancer research community to help discover new therapeutic strategies for cancer patients sooner.
TORONTO, ON (September 3, 2015) – Researchers from the Ontario Institute for Cancer Research (OICR) and the Structural Genomics Consortium (SGC) at the MaRS Discovery District in Toronto have developed a new drug prototype called OICR-9429 and made it freely available to the research community. Already research conducted by international groups using OICR-9429 has shown it to be effective in stopping cancer cell growth in breast cancer cell lines and a specific subtype of leukemia cells.
Significant time and resources are required to test new cancer treatments but unfortunately most ideas fail late in the development process and most of the activities are carried out in parallel, without sufficient collaboration. This leads to massive duplication of effort and ultimately increased cost of cancer drugs. By making early stage drug-like compounds such as OICR-9429 available, OICR and the SGC are allowing researchers to more rapidly test new treatment strategies and facilitate sharing of the results. Independent studies from Philadelphia and Vienna have now shown that the cellular target of OICR-9429 may be relevant for drug discovery.
“In the time that it would normally take to negotiate a legal agreement to provide OICR-9429 to other research teams we have received results back from our collaborators showing that it can kill two different types of cancer cells,” says Dr. Cheryl Arrowsmith, Chief Scientist at SGC Toronto. “Opening our chemistry capabilities to the world’s scientists allowed us to crowdsource and accelerate the research.” Dr. Arrowsmith is also a Professor in the Department of Medical Biophysics, Faculty of Medicine at the University of Toronto and a Senior Scientist, Princess Margaret Cancer Centre, University Health Network.
“It is remarkable how quickly our research results were translated into discoveries by the groups around the world. This demonstrates that Ontario is a new hub of a global drug discovery effort,” says Dr. Rima Al-awar, Director and Senior Principal Investigator, Drug Discovery Program, OICR. “We are looking forward to seeing more research conducted with OICR-9429 and showing that this new approach to early-stage drug discovery has significant advantages.”
OICR-9429 works to inhibit a protein called WDR5 and two recent studies evaluated its effect on breast cancer and leukemia cell lines and returned encouraging results.
A study led by Dr. Shelly Berger at the University of Pennsylvania used OICR-9429 to stop cancer cell growth in a panel of breast cancer cell lines driven by mutated forms of the gene p53. In its normal form p53 is a tumour-suppressor, however once it is mutated it leads to a ‘gain of function’ and causes cancers to grow though its stimulation of WDR5 function. This research is significant as p53 is mutated in at least half of all cancers and is dysregulated in others.
A team headed by Drs. Florian Grebien and Giulio Superti-Furga at the CeMM Research Center for Molecular Medicine in Vienna, Austria used OICR-9429 to demonstrate the potential of WDR5 as a therapeutic target for leukemia. Their research showed that OICR-9429 stopped the growth of leukemia cells with a very specific mutation found in about nine per cent of patients with acute myeloid leukemia.
These two studies culminated in joint publications, in Nature and Nature Chemical Biology respectively, between the international researchers and the Ontario-based OICR and SGC teams.
“I applaud this innovative partnership between OICR and SGC and their collaborative efforts to catalyze cancer research worldwide,” says Reza Moridi, Ontario Minister of Research and Innovation. “Collaboration, both at home in Ontario and abroad, is key to driving scientific discoveries and ultimately delivering better care to cancer patients.”
OICR-9429 is just one in a series of drug-like compounds developed by the SGC that are enabling a new approach to early-stage drug discovery. The SGC and OICR teams are continuing their collaboration to identify additional drug-like molecules to advance cancer drug discovery.
July 28, 2015
The Centre for Drug Research and Development (CDRD) and the Ontario Institute for Cancer Research (OICR) team up to advance cutting-edge new cancer treatments
Vancouver, BC and Toronto, ON – July 28, 2015: Two of Canada’s leading drug research and commercialization centres have announced a call for proposals to help bring new cancer treatments to patients through collaborative technology-development projects from academic investigators across Canada.
The Centre for Drug Research and Development (CDRD) and the Ontario Institute for Cancer Research (OICR) are providing opportunities for Canadian academic investigators at the cutting edge of cancer research to translate and advance their early-stage technologies and discoveries through pre-clinical development in order to ultimately bring new therapies to patients.
This unique partnership offers unprecedented access to commercialization resources and infrastructure to de-risk and validate new disease-modifying therapies for oncology. The partners are looking to collaborate on projects that will advance the preclinical development of novel therapeutics that focus on innovative targets or therapeutic approaches including small molecules, biologics and cell based therapies.
Unlike traditional grants, CDRD and OICR will work in partnership with academic investigators to develop collaborative project plans addressing the critical steps that are required to advance cancer therapies from the lab towards the clinic and patients who will benefit. Projects will be milestone-driven with clear go/no-go decision points with budgets depending on the scope of the project.
CDRD President and CEO, Karimah Es Sabar commented, “We are very pleased to be partnering with OICR, and to be bringing together resources from across the country to help bring new cancer treatments to the market. By utilizing and leveraging our complementary expertise and infrastructure, we are excited to be accelerating the development of safe and effective treatments for cancer patients.”
Dr. Rima Al-awar, Director of OICR’s Drug Discovery Program said, “Collaboration is essential to bringing innovative research ideas to patients. OICR is proud to partner with the CDRD to help academic investigators move their most promising discoveries to the clinic and to help move cancer research forward.”
The program is open and currently seeking pre-proposals. More information can be found here: www.cdrd.ca/news.