February 19, 2021
Inhibiting a key enzyme could help stop the growth of glioblastoma
Fewer than 10 per cent of people diagnosed with glioblastoma will survive beyond five years. Despite advances in understanding this deadly brain cancer, therapy options for this disease are severely limited. In a study recently published in Nature Communications, researchers have discovered that inhibiting a key enzyme, PRMT5, can suppress the growth of glioblastoma cells. Their findings demonstrate a novel approach to treating the disease, paving the way for a new class of therapeutics.
A multidisciplinary team with expertise in cancer stem cells, protein structures, small molecule development and multi-omic analyses enabled this discovery. The group, was co-led by Dr. Peter Dirks, Senior Scientist and Neurosurgeon at the Hospital for Sick Children (SickKids) and co-leader of OICR’s Brain Cancer Translational Research Initiative along with researchers at the Princess Margaret Cancer Centre, the Structural Genomics Consortium (SGC) and the University of Toronto. Many of the researchers involved in the study are also part of the Stand Up To Cancer (SU2C) Canada Cancer Stem Cell Dream Team, which receives support from OICR.
Through the study, they showed that inhibiting PRMT5 affected a large network of proteins that are important in cell division and growth, triggering cell senescence, and stopping the unrelenting division of cancer cells.
While PRMT5 inhibition has been previously suggested as a way to target brain and other cancers, no one has tested this strategy in a large cohort of patient tumour-derived cells that have stem cell characteristics, cells that are at the roots of glioblastoma growth.
They found that specific molecules – precursors to actual therapeutic drugs – inhibited the same enzyme, PRMT5, stopping the growth of a large portion of these patient-derived cancer stem cells. Many current drugs do not eliminate cancer stem cells, which may be why many cancers regrow after treatment.
“We used a different strategy to stop cancer cells from proliferating and seeding new tumours,” says co-senior author, Dr. Cheryl Arrowsmith, Senior Scientist at the Princess Margaret Cancer Centre who leads the University of Toronto site of the SGC. “By inhibiting one protein, PRMT5, we were able to affect a cascade of proteins involved in cell division and growth. The traditional way of stopping cell division has been to block one protein. This gives us a new premise for future development of novel, more precise therapies.”
“This strategy also has the opportunity to overcome the genetic variability seen in these tumours,” says co-senior author, Dirks, who also leads the SU2C Canada Dream Team. “By targeting processes involved in every patient tumour, which are also essential for the tumour stem cell survival, we side-step the challenges of individual patient tumour variability to finding potentially more broadly applicable therapies.”
The researchers also examined the molecular features of the patient-derived glioblastoma cells by comparing those that responded well to those that did not respond as well. They found a different molecular signature for the tumour cells that responded. In the future, this could lead to specific tumour biomarkers, which could help in identifying those patients who will respond best to this new class of drugs.
The research group will continue testing PRMT5 inhibitors to develop new therapies for people with glioblastoma.
“Right now, we have too few medicines to choose from to make precision medicine a reality for many patients,” says Arrowsmith. “We need basic research to better understand the mechanism of action of drugs, particularly in the context of patient samples. This is what will help us develop the right drugs to give to the right patients to treat their specific tumours.”
The research group also included OICR-affiliated scientists and staff researchers, Drs. Trevor Pugh, Mathieu Lupien, Benjamin Haibe-Kains, and Ahmed Aman.
Adapted from a SickKids news release.
August 25, 2020
OICR-supported researchers demonstrate new drug may eliminate triple negative breast cancer cells in certain patients, discover a new method to identify which patients will benefit
Adapted from UHN’s Media Release.
Triple negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that often spreads to other organs and accounts for one in four breast cancer deaths. OICR-supported researchers at the University Health Network’s Princess Margaret Cancer Centre are zeroing in on the molecular mechanisms that fuel this deadly cancer’s runaway growth to develop more effective treatments for this disease.
In their study, recently published in Nature Communications, they found a promising approach that could potentially identify the patients who could benefit from a more precise, targeted therapy for TNBC.
“This disease has no precision medicine, so patients are treated with chemotherapy because we don’t have a defined therapeutic target,” says co-lead of the study Dr. Mathieu Lupien, Senior Scientist at the Princess Margaret Cancer Centre and OICR Investigator. “Initially, it works for some patients, but close to a quarter of patients recur within five years from diagnosis, and many develop chemotherapy-resistant tumours.”
“These savage statistics mean that we must improve our understanding of the molecular basis for this cancer’s development to discover effective, precise targets for drugs, and a companion test to identify which patients are most likely to benefit the most from such a therapy.”
The study investigated how TNBC cells are dependent on a specific protein called GLUT1 and its associated molecular pathways. Prior studies suggested that TNBC cells were dependent on GLUT1, but this study is the first to demonstrate that blocking GLUT1 function may be an effective therapeutic strategy for certain patients with TNBC.
Using a collection of cell lines, the researchers found that blocking this pathway with a drug-like chemical compound “starved” the cancer cells, but only in a subset of TNBC patient samples. The group investigated further and found a common trait between the cell lines that were sensitive to the drug – they had high levels of a protein called RB1. This indicates that patients with TNBC and high levels of RB1 may, one day, benefit from this drug.
“Having access to diverse cell models of triple-negative breast cancer allows us to distinguish where the potential drug will work, and where it won’t,” says Lupien. “Without this broad spectrum of samples, we might have missed the subset of triple-negative breast cancers that respond to our compound.”
Collectively, this study suggests that clinical evaluation of targeting GLUT1 in certain patients with TNBC is warranted.
“The more we understand about the molecular complexity of cancer cells, the more we can target with precision,” says co-lead of the study Dr. Cheryl Arrowsmith, Chief Scientist for the Structural Genomics Consortium Toronto laboratories and Professor of Medical Biophysics at the University of Toronto. “And the more we can build up a pharmacy of cancer drugs matched to specific changes in the cancer cell, the greater the chance of a cure.”
Read UHN’s Media Release.
February 12, 2016
Doing things differently: The story behind the promising chemical probe developed by OICR and the Structural Genomics Consortium
A recent collaboration between researchers at OICR and the Structural Genomics Consortium (SGC) used a new open-source approach to early stage drug discovery to develop and share without restrictions a drug-like molecule (or chemical probe) called OICR-9429 in an effort to crowd-source cancer research. OICR-9429 specifically inhibits a protein called WDR5 and can be used to investigate its function in a cell.
“Testing a new cancer treatment takes significant time and resources and unfortunately many attempts fail late in the development process. Also, most of the research activities are carried out in parallel and without enough collaboration. This leads to the duplication of a great amount of effort and raises the cost of cancer drugs that do make it to the clinic,” explains Dr. Cheryl Arrowsmith, Chief Scientist at SGC Toronto.
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.