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.
July 24, 2019
OICR funding for Ontario drug discovery projects will accelerate development of new cancer therapies
The Ontario Institute for Cancer Research (OICR) has selected two new Late Accelerator projects to receive support through its Cancer Therapeutics Innovation Pipeline (CTIP) initiative. The projects, detailed below, will each receive up to $250,000 per year, for up to two years, to advance the development of drug candidate molecules. The projects were selected by an international expert review panel from 18 applications.
By joining the CTIP portfolio, these projects will receive more than just financial support – they will also benefit from the guidance of the Therapeutics Pipeline Advisory Committee, a group of industry and academic experts that provides advice on the scientific and strategic direction of CTIP projects.
“CTIP projects have great potential to improve treatment for patients, promote scientific collaboration and drive investment to Ontario’s biomedical research sector,” says Dr. Christine Williams, OICR’s Deputy Director and Head of Therapeutic Innovation. “These new projects are great examples of the innovative cancer therapeutics research happening in our province. We are excited to add them to CTIP’s portfolio of promising drug candidates and look forward to their progress.”
Identification of kinase inhibitors to block the tumour-promoting activity of YAP/TAZ for cancer therapeutics
Liliana Attisano, Principal Investigator, University of Toronto
Rima Al-awar, Principal Investigator, OICR
Frank Sicheri, Co-investigator, Lunenfeld-Tanenbaum Research Institute
Jeff Wrana, Co-investigator, Lunenfeld-Tanenbaum Research Institute
David Uehling, Co-investigator, OICR
Richard Marcellus, Co-investigator, OICR
Methvin Isaac, Co-investigator, OICR
The highly conserved Hippo pathway is a key regulator of cell and tissue growth. Virtually all solid tumours display pathway disruptions, which drive cancer initiation and progression. Mutations in pathway components are rare, making it unclear how to target the pathway for cancer treatment. This research group has shown that certain kinases are key regulators of the pathway that promotes tumorigenicity and observed that diverse human cancers display elevated levels of these kinases. Kinases are highly amenable to the development of targeted inhibitors; therefore, this project will identify potent and specific inhibitors with the long-term goal of establishing novel cancer therapeutics.
Development of kinase inhibitors for ovarian cancer: A novel first in-class immune-oncology therapeutic agent targeting tumor intrinsic stress states
Rob Rottapel, Principal Investigator, Princess Margaret Cancer
Tracy McGaha, Principal Investigator, Princess Margaret Cancer
Rima Al-awar, Principal Investigator, OICR
Methvin Isaac, Co-investigator, OICR
David Uehling, Co-investigator, OICR
Richard Marcellus, Co-investigator, OICR
Ahmed Aman, Co-investigator, OICR
The development of new cancer immune therapeutics has triggered a revolution with the recent advent of diverse strategies that engage the patient’s immune system. This research group has identified a novel kinase target that has the unique property of being both an emergent essential gene in high-grade serous ovarian cancer and a repressor of the innate and adaptive immune system. Additionally, they have demonstrated that target inhibition sensitizes cancer cells to cisplatin – a standard of care chemotherapy drug. This project will work to develop a “first-in-class” dual-action, anti-tumour and immune-oncology kinase inhibitors for ovarian cancer and potentially other cancer types.
May 21, 2019
Dr. Brigitte Thériault, a Senior Research Scientist at OICR, discusses the work of the Drug Discovery team to develop new drugs that awaken the body’s immune system to recognize and attack cancer cells.
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 21, 2019
OICR supports cancer drug discovery in Ontario with new funding for four promising early-stage projects
Toronto (February 21, 2019 | Updated July 15, 2019) – The Ontario Institute for Cancer Research (OICR) today announced that three Early Accelerator projects from across Ontario will each receive $100,000 for one year as part of OICR’s Cancer Therapeutics Innovation Pipeline (CTIP) initiative. The funding will be used to validate cancer targets and support experiments to screen molecules against these targets, finding those that can bind to them successfully and have potential to be developed into medicines.Continue reading – OICR supports cancer drug discovery in Ontario with new funding for four promising early-stage projects
January 29, 2019
First-in-class drug for blood cancers discovered by Ontario researchers receives record-setting industry investment
Years of hard work by OICR’s Drug Discovery group and Ontario partners moves potential new treatment for leukemia towards clinical trials
On January 29, 2019, Celgene Corporation made an investment of up to US$1 billion that will facilitate further research and development of the potential drug and support clinical trials in Ontario. The potential drug was designed to exploit a weakness in leukemia centred on the protein WDR5 that was discovered by Ontario researchers. If all options under the investment are exercised, the deal will be the largest transaction to date for a preclinical asset discovered in Canada.
“The progress of this pre-clinical drug towards the clinic is an example of how OICR, working with its partners, is accelerating cancer research in Ontario and increasing investment so that new innovations can help patients as soon as possible,” says Dr. Laszlo Radvanyi, President and Scientific Director of OICR. “This announcement shows how OICR and FACIT’s unique model for research and commercialization can generate long-term impact for the province of Ontario.” FACIT is OICR’s strategic commercialization partner.
The WDR5 project’s development demonstrates the unique expertise of OICR DD, the advantages to the OICR-FACIT model, and how OICR effectively harnesses the strengths of Ontario’s diverse cancer research ecosystem by collaborating with groups such as the Structural Genomics Consortium (SGC), the group that initially identified the potential of targeting WDR5 as a treatment for cancer.Continue reading – First-in-class drug for blood cancers discovered by Ontario researchers receives record-setting industry investment
September 13, 2018
Prospects Oncology Fund seeds developing pipeline of Ontario-based biotech innovations
TORONTO, ON (September 13, 2018) – With an expanding portfolio of breakthrough innovations, FACIT is committed to supporting Ontario entrepreneurs through the latest round of its Prospects Oncology Fund. FACIT has selected three novel cancer therapeutic discoveries to receive early-stage capital – biotechnology start-up Talon Pharmaceuticals (“Talon”), the Drug Discovery team at the Ontario Institute for Cancer Research (“OICR”) and CCRM. The Prospects Fund provides entrepreneurial scientists with the capital resources necessary to achieve critical proof-of-principle studies for their cutting-edge breakthroughs aiming to benefit future patients.
September 4, 2018
Meet Dike Aduluso-Nwaobasi, Sarah Donald and Benson Wan. Find out how summer co-op positions affected their career and educational journeys.
August 22, 2018
Ratheesh Subramaniam talks about his work in OICR’s Drug Discovery team and how it could help doctors make a difference in treating cancer patients.
July 31, 2018
OICR-funded drug discovery project’s unique ‘open science’ business model is accelerating the search for a solution to lethal pediatric brain cancers
Diffuse intrinsic pontine glioma (DIPG) is a lethal and inoperable brain cancer with a median survival of less than a year from diagnosis. Finding solutions to this disease is challenging due to its rarity, scientific complexity and its presentation in pediatric populations. An OICR-funded team of researchers, led by Dr. Aled Edwards from M4K Pharma, have developed new potential drug candidates for DIPG that they will test in animal models in the coming months. They’ve reached this milestone ahead of schedule, with fewer resources required than anticipated, by using an ‘open drug discovery’ approach – sharing their methods and data with the greater research community to streamline the drug discovery process.
December 4, 2017
OICR launches groundbreaking Cancer Therapeutics Innovation Pipeline to drive cutting-edge therapies to the clinic
Ten new projects were selected in the pipeline’s inaugural funding round, highlighting Ontario’s strengths in collaboration and drug discovery.
Toronto (December 4, 2017) – The Ontario Institute for Cancer Research (OICR) today announced the Cancer Therapeutics Innovation Pipeline (CTIP) initiative and the first 10 projects selected in CTIP’s inaugural round of funding. CTIP aims to support the local translation of Ontario discoveries into therapies with the potential for improving the lives of cancer patients. The funding will create a new pipeline of promising drugs in development, and attract the partnerships and investment to the province necessary for further clinical development and testing.
“Ontario congratulates OICR on this innovative approach to driving the development of new cancer therapies,” says Reza Moridi, Ontario’s Minister of Research, Innovation and Science. “The Cancer Therapeutics Innovation Pipeline will help ensure that promising discoveries get the support they need to move from lab bench to commercialization, and get to patients faster.”