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.