May 13, 2020
Toronto researchers unravel key cancer-driving circuit between the “powerhouse” and the “brain” of leukemia cells, in big first step for future therapeutic discovery and development
Over the last few decades, research has suggested that mitochondria, also known as the “powerhouses of the cell”, play an important role in tumour growth and development, but little is known about how to prevent these cellular machines from wreaking havoc. In a recent study, scientists have discovered a key protein that is made in the “powerhouse of the cell”, unexpectedly affects the expression of genes in the nucleus, or the “brain”, of certain leukemia cells. The study was launched by Dr. Dilshad Khan, who – alongside colleagues in Dr. Aaron Schimmer’s lab at the Princess Margaret Cancer Centre – set out to determine which genes in the mitochondria were essential to the growth and viability of acute myeloid leukemia (AML).
Through genome-wide CRISPR screening and other gene-manipulating techniques, they discovered a key mitochondrial protein that AML cells can’t survive without – MTCH2. Their findings, which were recently published in Blood, may eventually lead to new ways to fight this common and fast-growing form of blood cancer.
“We found that the mitochondrial protein MTCH2 is essential for the growth and survival of AML cells,” says Khan, Postdoctoral Fellow in the Schimmer Lab, who is the first author of the study. “But finding this protein was just one piece of the puzzle. We needed to understand how it worked.”
With Khan’s expertise in epigenetics, the team systematically dissected how MTCH2 affects AML cells. They found that blocking this protein would ultimately cause leukemic stem cells – the difficult-to-treat renewable cells that are thought to be at the root of leukemia – to irreversibly transform into cells that are easier to eliminate with existing chemotherapies.
“Through a series of experiments, we unraveled how MTCH2 affects AML cells and discovered that this protein has a remarkable and unexpected impact on nuclear pathways – it could control nuclear gene expression to affect AML stemness and survival,” says Khan. “We never thought this could happen, but now that we’ve discovered these new links, we could potentially find new ways to control these mechanisms.”
Next, the Schimmer Lab and collaborators plan to investigate MTCH2’s specific mechanism to find where inhibitors – or potential cancer drugs – could block its path. These initiatives will add to Schimmer’s research on dysregulated mitochondrial pathways in leukemia, including his recent work on fat production and copper distribution in leukemic stem cells. This research is funded in part by OICR’s Acute Leukemia Translational Research Initiative and OICR’s Cancer Therapeutics Innovation Pipeline.
“This study showed us that mitochondrial proteins are more interconnected with other cellular networks than we thought,” says Khan. “These fundamental findings have shed light on new research avenues that we can pursue to find new solutions that will hopefully benefit patients with AML.”
April 24, 2019
Collaborative research group discovers a key pathway in the development of acute myeloid leukemia – and a potential new therapeutic strategy to treat the disease
Despite progress in the treatment of acute myeloid leukemia (AML), many patients still die from relapse or experience significant side effects from treatment. Dr. Aaron Schimmer, who is Research Director of the Princess Margaret Cancer Centre and co-lead of OICR’s Acute Leukemia Translational Research Initiative, worked with his collaborators to understand the root cause of AML relapse to develop more effective and less toxic therapies. Their recent findings are both surprising and promising.
The group, which consists of researchers from across Ontario and abroad, investigated the pathways that are uniquely important to the growth and development of leukemic stem cells (LSCs) – also known as the cells at the “root” of the disease. They discovered a key pathway, as described in Cell Stem Cell, which can be altered to control how LSCs mature. Interestingly, they found that this process can be modulated with an essential phospholipid (a type of fat), called phosphatidylserine.
“We discovered a pathway that these stem cells rely on. We investigated further and found that interfering with lipid metabolism – that is, the fats within these cells – could potentially slow their growth and reduce their ability to cause relapse,” says Ayesh Seneviratne, MD/PhD candidate in the Schimmer Lab at the University of Toronto and co-first author of the publication.
Normally, phosphatidylserine is important in maintaining the integrity of the cell membrane and normal cell function, but the authors found that within LSCs, phosphatidylserine acted as a trigger for the cell to lose its self-renewal properties. They are the first group to describe increasing phosphatidylserine as a potential therapeutic strategy for AML.
“We now better understand the function of this metabolite in leukemia, and in turn, we have found a new way to target the disease,” says Dr. Mingjing Xu, postdoctoral fellow in the Schimmer Lab and co-first author of the publication. “We are enthusiastic to pursue further studies and unravel how phosphatidylserine ceases leukemia growth.”
Schimmer says that this work could not have been done without the contributions of many collaborators.
“This discovery is a product of a concerted effort between many researchers,” says Schimmer. “Together, we’ve found new insights into the biology of leukemia and turned those insights into a new potential therapeutic strategy.”
July 11, 2017
The rising use of stem cell-based therapies has illustrated the power of stem cells to treat a number of diseases. Now a group of Ontario researchers are looking at the promise of stem cells from a different perspective. Amongst other efforts, they are developing and testing new therapies that target and kill leukemic stem cells to lessen the chances of acute leukemias (AL) coming back following standard treatment.
May 25, 2017
OICR launches five all-star teams of Ontario scientists to tackle some of the deadliest forms of cancer
Great strides have been made in cancer research, but much work remains to develop better treatments for the most lethal cancers and to advance new anti-cancer technologies. OICR is taking on a new approach, building on the success of the Institute’s first ten years and Ontario’s strength in particular cancer research areas. Reza Moridi, Ontario’s Minister of Research, Innovation and Science announced that the Institute is funding five collaborative, cross-disciplinary and inter-institutional Translational Research Initiatives (TRIs) with a total of $24 million over the next two years.
The TRIs will bring together some of the top cancer researchers in Ontario and be led by internationally renowned Ontario scientists. Each team will focus on a certain type of cancer or therapeutic technology. To maximize the positive impact of research on patients, the TRIs all incorporate clinical trials into their design. The TRIs, which were selected by an International Scientific Review Panel, are:
- Acute Leukemia TRI (led by Drs. John Dick and Aaron Schimmer at the University Health Network (UHN))
- Brain Cancer TRI (led by Drs. Peter Dirks and Michael Taylor at SickKids)
- Immuno-oncology TRI (ACTION) (led by Drs. John Bell and Marcus Butler at The Ottawa Hospital and UHN)
- Ovarian Cancer TRI (led by Drs. Amit Oza and Rob Rottapel at UHN)
- Pancreatic Cancer TRI (PanCuRx) (led by Dr. Steven Gallinger at UHN)
The funding will also support Early Prostate Cancer Developmental Projects led by Drs. Paul Boutros and George Rodriguez.
“In just over 10 years, the Ontario Institute for Cancer Research has become a global centre of excellence that is moving the province to the forefront of discovery and innovation in cancer research. It is home to outstanding Ontario scientists, who are working together to ease the burden of cancer in our province and around the world,” said Moridi.
“Collaboration and translational research are key to seeing that the innovative technologies being developed in Ontario reach the clinic and help patients,” said Mr. Peter Goodhand, President of OICR. “These TRIs represent a unique and significant opportunity to impact clinical cancer care in the province.”
— SickKids_TheHospital (@SickKidsNews) May 25, 2017
— UHN (@UHN_News) May 25, 2017
— The Ottawa Hospital (@OttawaHospital) May 25, 2017
May 25, 2017
OICR launches five large-scale Ontario research initiatives to combat some of the most deadly cancers
Toronto (May 25, 2017) – Reza Moridi, Ontario’s Minister of Research, Innovation and Science, today announced the Ontario Institute for Cancer Research is launching five unique, cross-disciplinary, multi-institutional Translational Research Initiatives (TRIs), each focused on a single type of or treatment approach to cancer. With $24 million in funding over two years, the TRIs will bring together world-leading scientists to tackle some of the most difficult to treat cancers and test innovative solutions to some of the most serious challenges in cancer today.
The TRIs build on Ontario’s proven strengths in areas such as stem cells, immuno-oncology, pediatric cancers, genomics, clinical trials and informatics. Working together, the province’s top scientists and clinicians will accelerate the development of much needed solutions for patients around the globe, with a focus on acute leukemia and brain, ovarian and pancreatic cancers. Each TRI includes clinical trials to maximize patient impact.
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.