March 12, 2020
Toronto-based research team uncovers dozens of rare mutations found in head and neck cancers converge on a single molecular pathway, amplifying the need to shut down this critical cancer-causing mechanism
With the advancement of DNA sequencing technology, researchers have discovered hundreds of genes that, when mutated, can drive cancer progression. Despite these discoveries, we don’t yet fully understand how the majority of cancer-causing genes work, leaving a large gap between the discovery of a gene mutation and the discovery of a new therapy. Dr. Daniel Schramek is filling that gap.
In a recent study, published in Science, Schramek and collaborators, including Dr. Trevor Pugh, Director of Genomics at OICR, analyzed the function of nearly 500 gene mutations found in head and neck cancers. Remarkably, they discovered that the many of these mutations affected one key molecular process within cancer cells. They shut down NOTCH signaling.
“While we see many different mutations in different genes across different patients, we found that many mutations, surprisingly, tend to do the same thing,” says Schramek, who is an investigator at Sinai Health’s Lunenfeld-Tanenbaum Research Institute (LTRI). “This means the complexities of head and neck cancers may be simpler than we thought”
Schramek reasons that focusing on correcting the NOTCH pathway, rather than correcting the effects of each individual gene mutation, could simplify and focus the search for new and improved cancer therapies. He estimates that approximately 70 per cent of people with head and neck cancers have tumours that are affected by this pathway. Thus, a large majority of these patients could benefit from NOTCH-correcting cancer drugs.
“Every patient’s tumour is made up of different gene mutations and combinations of these mutations,” says Dr. Sampath Loganathan, first author of the study and Postdoctoral Fellow in the Schramek Lab. “Some of the more common, well-understood mutations are druggable – meaning they can be blocked with drugs – but there are hundreds of rarer, but important, mutations that we don’t yet understand.”
It is challenging to understand how a single mutation causes damage within a cell and ultimately leads to cancer. It is tremendously more challenging to understand the function of hundreds of mutations.
Our findings present a new way of thinking about precision oncologyDr. Daniel Schramek
Schramek’s lab, however, developed an experimental system that allowed them to accelerate traditional functional testing for a fraction of the cost. Their system could test hundreds of gene mutations in a single mouse model. What would take several millions and decades in research and development, could now be done in one year for a fraction of the cost. Equipped with their powerful tools, this research group was the first to systematically look at rare mutations in head and neck cancers.
Schramek and collaborators are now working to identify key elements within the NOTCH pathway that can be blocked with chemicals. Their ultimate goal is to develop these chemicals into new drugs to help those with head, neck and other types of cancers. They will also continue to explore this phenomenon in other cancers such as breast and pancreatic cancers.
“Our findings present a new way of thinking about precision oncology,” Schramek says. “Instead of matching patients with specific mutations to specific treatments, researchers could focus on shutting down or restoring the pathways involved with those genes – hence, a pathway-centric model of precision oncology. We’re excited by this progress, and we look forward to bringing our ideas to future patients.”
This research was done in collaboration with OICR and was supported by the Canadian Institutes of Health Research, the Terry Fox Research Institute and the Human Frontier of Science Program. Schramek is a Kierans/Janigan Cancer Research Scientist and holds a Canada Research Chair in functional cancer genomics in the Department of Molecular Genetics at the University of Toronto.
Read more about this work in the Lunenfeld-Tanenbaum Research Institute’s news story.
August 9, 2017
A newly published paper in Genetics in Medicine has reinforced the fundamental importance of collecting information about genetic variances in a single large database. With so much important genetic information being used globally to understand the underlying genetic influences of diseases, researchers and clinicians need an accessible repository to share this information.
March 16, 2017
Genetic tests are being used more commonly in the diagnosis of many types of cancer. However, there currently isn’t a highly accurate test that can identify men with aggressive forms of prostate cancer, making it more difficult to choose the most appropriate course of treatment.
February 10, 2017
OICR researchers to be part of Cancer Research UK’s Grand Challenge helping to answer cancer’s biggest questions
Toronto (February 10, 2017) – Ontario Institute for Cancer Research (OICR) researchers Drs. Lincoln Stein and Steven Gallinger have been announced as members of one of the first global research teams to be recipients of Cancer Research UK’s Grand Challenge.
The Grand Challenge aims to help overcome the biggest challenges facing cancer research in a global effort to beat cancer sooner.
Stein and Gallinger’s pioneering team will study samples from five continents to understand the DNA damage associated with different cancers, to understand what causes them and if they can be prevented. The project will be led by Professor Mike Stratton at the Wellcome Trust Sanger Institute, Cambridge, with collaborators from France, the U.S. and U.K.
September 21, 2016
New partnership brings Toronto researchers together to better understand the molecular origins of breast cancer
Researchers from the Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital have enlisted the help of OICR’s Transformative Pathology Program in their ongoing research to identify common biomarkers for breast cancer – and ultimately to better diagnose and target treatment for patients.
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.
January 7, 2016
Ontario Institute for Cancer Research invests $1.2 million to support oncology drug development in Ontario
Five promising early stage research projects that would benefit from OICR’s input and expertise were selected from a province-wide call for proposals.
Toronto (January 7, 2016) – Dr. Tom Hudson, President and Scientific Director of the Ontario Institute for Cancer Research (OICR) announced today that OICR will invest $1.2 million in funding, plus expertise and in-kind support, to help bring five promising oncology drug development projects closer to the clinic.
June 1, 2015
The Ontario Institute for Cancer Research invests $4.6 million to support pancreatic cancer research
TORONTO, ON (June 1, 2015) – Dr. Tom Hudson, President and Scientific Director of the Ontario Institute for Cancer Research (OICR) today announced OICR is investing $4.6 million over two years in PanCuRx, an initiative that seeks solutions to the high fatality rate of pancreatic cancer. The multidisciplinary program brings together researchers from the fields of genomics, pathology, cancer biology and informatics, as well as clinician scientists, who will collaboratively work to better understand pancreatic cancer on a molecular level and use this understanding to develop better, more personalized diagnostics and therapies for patients. The research will focus on pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer.
“There have been huge scientific advances over the past few decades on many types of cancer, but statistics on pancreatic cancer have remained largely unchanged,” said Dr. Tom Hudson, President and Scientific Director of OICR. “OICR is proud today to announce support for PanCuRx and help to improve these statistics and bring new solutions to patients.”
Initial funding for the initiative was provided last spring by Sylvia M. G. Soyka, director, and the Board of Trustees of the SMGS Family Foundation to the Canadian Friends of the Hebrew University (CFHU). The focus of this funding is to find and identify the molecular drivers behind metastatic pancreatic cancer. Researchers at the Institute for Medical Research Israel-Canada (IMRIC) at the Hebrew University of Jerusalem and Sheba Medical Center in Israel and at OICR in Toronto are currently working collaboratively to achieve this goal.
“This new funding will help tackle one of the least understood types of cancer. Ontario’s innovative and collaborative research community, together with our partners in Israel, are well suited for this challenge to discover new solutions and treatments that will benefit patients worldwide,” said Reza Moridi, Ontario Minister of Research and Innovation.
PanCuRx’s unique, collaborative design will allow teams of researchers to pursue research and clinical questions in parallel, with a tight link between clinical practice and lab research. The research will also be highly integrated with the Princess Margaret Cancer Centre’s translational PDAC program, ensuring that in addition to increasing understanding of the disease more generally, the research will directly inform the treatment strategy of patients who participate.
“The focus of PanCuRx is to ensure we bring the patients closer to the research and the research closer to the patients,” said Dr. Steven Gallinger, Surgical Oncologist and Head, Hepatobiliary/Pancreatic Surgical Oncology Program at University Health Network, Senior Investigator, Samuel Lunenfeld Research Institute of Mount Sinai Hospital and leader of the PanCuRx initiative. “By working together among disciplines and between the research and clinical components we feel much more can be accomplished and we have a real chance of making an impact on improving outcomes for PDAC patients.”
“I am alive today because of the groundbreaking treatment I received from Dr. Gallinger, Dr. Malcolm Moore and their team,” said Libby Znaimer, a prominent Canadian journalist and pancreatic cancer survivor. Znaimer received therapy targeted at the molecular level to the specific subtype of pancreatic cancer she was diagnosed with, an avenue of diagnosis and treatment that this new funding will further explore. “This summer I will celebrate seven years since diagnosis. We need more research to ensure that outcomes like mine become the norm, rather than a rare exception.”
Pancreatic ductal adenocarcinoma (PDAC) makes up approximately 85 per cent of pancreatic cancer cases. In 2014, an estimated 4,700 Canadians were diagnosed with PDAC and 4,400 died from the disease. It is the fourth leading cause of cancer death in Canada and the current five-year survival rate of 7.7 per cent is the lowest of all cancers. While the number of people dying from common cancers such as breast and colon cancer has dropped dramatically over the past 30 years, there have been only slight improvements for PDAC. It is estimated that PDAC will be the second leading cause of cancer death in North America within 10 years.