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.
December 14, 2018
As a radiation oncologist at the London Health Sciences Centre, Dr. David Palma is on the front lines of treating cancer patients with radiotherapy. Despite huge advances in radiation technology over the past few decades, Palma and his colleagues have noticed that clinical trials proving the benefits of these new technologies are not keeping pace – meaning these advances are not always reaching patients. To overcome these challenges and advance treatment, Palma formed the Canadian Pulmonary Radiotherapy Investigators Group (CAPRI) to support radiotherapy clinical trials and get them up and running as quickly as possible.Continue reading – Pan-Canadian radiotherapy group advancing care by reducing barriers to conducting clinical trials
December 11, 2017
Strict e-cigarette policies are meant to keep non-smokers from smoking. But they may also be preventing many smokers from quitting
Regulatory strategies on electronic cigarettes vary from country to country. The International Tobacco Control Policy Evaluation Project, led by Dr. Geoffrey Fong, explored how different regulatory environments might influence the effectiveness of e-cigarettes for smoking cessation. This research could be used to help shape e-cigarette control policies that minimize the potential health risks and recognize the potential benefits of e-cigarettes as a smoking cessation aid.
October 24, 2017
Brain tumours resulting from the spread of cancer from its primary location, known as brain metastases (BM), are the most common form of brain tumours in adults. A team of Ontario-based researchers recently identified two genes that seem to play a central role in BM in lung cancer patients – findings that could lead to improved biomarkers and treatments for BM.
In a study published in the journal Acta Neuropatologica, Mohini Singh and her collaborators focused on a class of cells they have termed Brain Metastases Initiating Cells (BMICs), which leave the primary site of cancer and migrate to the brain.
Singh, a biochemistry PhD candidate in the lab of Dr. Sheila Singh at McMaster University, explains the approach the team took to study these cells. “There was a lack of preclinical models that we could use to comprehensively study BMICs and understand the mechanisms behind them. To conduct our study we used brain metastases from lung cancer patients, which we cultured in conditions to enrich for BMICs, and then transplanted them into mice. This method allowed us to study BMICs within a living host, which provides a more accurate representation of the development of brain metastasis in humans.”
The researchers performed in vitro and in vivo RNA interference screens utilizing their unique BM models, and found two genes that were essential to the regulation of BMICs: SPOCK1 and TWIST2. “We discovered that SPOCK1 is a regulator of self-renewal in BMICs, playing a role in the initiation of lung tumours and their metastasis to the brain,” explains Singh. Furthermore, the results were clinically relevant. “Increased SPOCK1 expression was seen in lung cancer biopsies of patients with known brain metastases, and was correlated with poor survival.” Through protein-protein interaction mapping the researchers also identified new pathway interactors of the two genes that could be used as novel targets in treatment of BM in lung cancer patients.
“Identifying these two genes could be of great use in improving the treatment of lung cancer. In the future we could predict those patients who are most at risk of developing a brain metastasis and use drugs to target BMIC regulatory genes such as SPOCK1 and TWIST2 to destroy the initiating cells and to block the spread,” says Singh. “This would result in keeping the lung cancer locally controlled and therefore more treatable.”
OICR funding was used to establish this study with further significant funding coming from the Canadian Cancer Society and the Brain Canada Studentship.
August 17, 2017
Research from McMaster University has identified new regulators of brain metastases in patients with lung cancer.
These regulators are the genes called SPOCK1 and TWIST2.
May 31, 2017
According to the World Health Organization (WHO), tobacco is used by over 1 billion people and is the number one preventable cause of death and disease. Tobacco—especially smoked tobacco—causes 30 per cent of the world’s cancer cases and so tobacco control is the number one strategy for preventing cancer. Tobacco use kills six million people a year. It also brings a staggering economic cost of US$1 trillion a year in health care expenditures and lost productivity.
The WHO Framework Convention of Tobacco Control (FCTC) is a treaty that was created to combat the global tobacco epidemic. Currently, 179 countries and the European Union have joined the treaty, which obligates countries covering about 90 per cent of the world’s population to implement a set of strong evidence-based measures to reduce tobacco use. The FCTC is, in effect, the most extensive cancer prevention effort in history. The FCTC recently marked ten years since its coming into force. But how much impact have these measures made? A research team centered at the International Tobacco Control Policy Evaluation Project (the ITC Project), University of Waterloo (UW), recently published a study that demonstrated the positive impact of the FCTC on smoking rates.
Dr. Shannon Gravely, Research Assistant Professor at UW, was the lead author on the study, which was published in Lancet Public Health in March. The study examined how the implementation of five key FCTC tobacco policies affected smoking prevalence across 126 countries. “We looked at the highest-level implementation (i.e. fully satisfying the requirements of the FCTC) of these measures between 2007-2014 and the smoking prevalence estimates for the first 10 years of the FCTC, from 2005 to 2015,” says Gravely. “We found a strong and statistically significant association between the number of these FCTC measures and decreases in smoking rates.”
The five tobacco demand-reduction measures studied by the ITC Project team were: 1) Taxation; 2) Smoke-free policies; 3) Warning labels; 4) Bans on advertising, promotion and sponsorship; and 5) Cessation programs. The researchers found that with each additional measure implemented at its highest level, countries experienced an average decline in smoking prevalence of 1.57 percentage points, or a relative decrease of 7.09 per cent.
“It is indeed good news that the FCTC measures are associated with decreasing the number of smokers, but the bad news is that few countries are actually implementing these effective measures,” says Gravely. Only a fifth of the countries covered in the study had implemented taxes on tobacco at the highest levels called for under the treaty. “We found this to be particularly worrisome as it is known that increasing the price of tobacco via taxes is the most effective way to reduce tobacco use,” says Gravely. In fact, none of the five key FCTC policies had been implemented by even half of the countries.
“Overall, the study found that these measures, when implemented at their highest levels are very effective at reducing smoking rates,” comments Gravely. “Our findings highlight the importance of tobacco control measures in improving global health by directly decreasing the rates of smoking thus in turn indirectly reducing tobacco-attributed-non-communicable diseases.”
Dr. Geoffrey Fong, Professor of Psychology and Public Health and Health Systems at UW and OICR Senior Investigator, is Chief Principal Investigator of the ITC Project. Fong, a co-author of the article, commented, “This study should be a call to arms for governments to strengthen and accelerate their efforts to fully implement the FCTC secure in knowing that such efforts will significantly reduce the devastation caused by tobacco products in their countries.”
August 11, 2016
OICR’s Geoff Fong receives major funding to examine e-cigarettes and the impact of public health policy
Around the world it has become common to walk down the street and see a new trend – people vaping (using e-cigarettes). The widespread use of e-cigarettes has caught the attention of the scientific community. Recently, OICR Investigator Dr. Geoff Fong was awarded funding from Canadian and U.S. federal funding agencies to evaluate the impact of e-cigarettes and determine the effectiveness of policies around their use.
May 31, 2016
For many years, smoking was considered a sophisticated and glamorous pastime advertised to millions as a source of relaxation and freedom. But today, in the face of decades of research showing the harmful short and long-term side effects of smoking, including cancer and lung disease, that perception has almost entirely disappeared.
Yet many people continue to smoke. Almost 15 per cent of Canadians (more than four million people) were active smokers in 2013, with the majority of smokers reporting that they smoked daily. Tobacco use is the leading cause of cancer and cancer deaths in the world and it contributes to many other serious health conditions. According to the World Health Organization (WHO), tobacco kills approximately six million people per year globally. Preventing the use of tobacco and helping users quit are the important first steps in a long-term effort to ensure fewer people develop and die from lung cancer and other related diseases.