September 16, 2020
Scientists discover mechanism of bone loss caused by acute lymphocytic leukemia, identify targeted therapy for children
OICR-supported research team discovers new pathway through which leukemia cells damage bone and a treatment that may protect children with leukemia from these effects
Due to remarkable progress in the treatment of pediatric leukemias with multi-drug chemotherapy, upwards of 85 per cent of children with the disease survive. One consequence of this success, is that more than a third of these patients suffer from in-bone fractures and pain during leukemia and for years following their treatment. In a recent study, Ontario researchers at the Hospital for Sick Children (SickKids) have discovered a process by which leukemia cells damage bone and discover that a targeted therapy may be able to prevent this damage.
In their study, published in Science Translational Medicine, the research group discovered that the bone degradation in leukemia patients is triggered by a protein called RANKL on the surface of the leukemic cells interacting with receptors called RANK on the surface of bone-degrading cells. The group showed that a drug, which is similar to one that is currently in clinical trials for other cancers, could specifically block this RANKL-RANK interaction and prevent further bone damage.
“A pan-Canadian study demonstrated that 15 per cent of children display bone fractures at the time they are diagnosed with acute lymphocytic leukemia, or ALL,” says lead author Dr. Jayne Danska, Senior Scientist in the Genetics & Genome Biology program at SickKids and Associate Chief, Faculty Development and Diversity at the SickKids Research Institute. “In addition, standard ALL chemotherapy protocols include corticosteroids which further damage the bone. Survivors of childhood ALL experience fractures and pain, and some cases are so severe that they require a hip replacement in their teenage years. We have discovered one mechanism that contributes to ALL-associated bone damage and a potential way to prevent it.”
To make these discoveries, first author of the study, Dr. Sujeetha Rajakumar, a postdoctoral fellow at SickKids, transplanted ALL cells from patient donors into experimental mouse models to examine the effect of leukemia cells on bone and how to disrupt the RANKL-RANK interaction. This so-called xenotransplantation method was pioneered by Dr. John Dick at the University Health Network’s Princess Margaret Cancer Centre.
Using these animal models, Danska’s group showed that treatment of the ALL-transplanted mice with a protein therapeutic that blocks the RANKL-RANK interaction prevented bone damage despite high number of leukemia cells in the bone compartments.
“There are clinical trials underway to test whether RANKL-RANK antagonists can prevent bone degradation in adults with metastatic prostate and breast cancers,” says Danska, who is also a Professor in the University of Toronto’s Faculty of Medicine. “The data we report in the human ALL transplant model is encouraging because the availability of clinical data with this class of drug can accelerate application of our discoveries to clinical trials in youth with ALL.”
“Children with leukemia sustain unbelievably rigorous and lengthy chemotherapy treatments,” says Danska. “We’re eager to bring our discoveries into clinical trials that may help minimize these painful and life-altering late effects of this disease.”
Danska and study collaborators Drs. Cynthia Guidos and Johann Hitzler of SickKids, and Drs. Mark Minden and John Dick of the Princess Margaret Cancer Centre are members of OICR’s Acute Leukemia Translational Research Initiative (TRI), which partially funded the study.
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.”
March 2, 2020
Researchers find the roots of leukemia relapse are present at diagnosis, uncovering clues to new treatment approaches
Despite significant advances in the treatment of acute lymphoblastic leukemia (ALL), the disease often returns aggressively in many patients after treatment. It is thought that current chemotherapies eliminate most leukemia cells, but groups of resistant cells may survive therapy, progress and eventually cause relapse. Dr. John Dick and collaborators have found these cells.
In a recent study published in Cancer Discovery, Dick and collaborators were able to identify and isolate groups of genetically distinct cells that drive ALL relapse.
The cells, termed diagnosis relapse initiating (dRI) clones were found to have genetic characteristics that differ from the other leukemia cells that are eliminated by treatment.
The study, along with a complementary study published in Blood Cancer Discovery, unraveled the genetic, epigenetic, metabolic and pro-survival molecular pathways driving treatment resistance. Together, these papers provide an integrated genomic and functional approach to describing the underlying genetics and mechanisms of relapse for ALL.
Interestingly, the research group discovered that dRI clones are present at diagnosis, opening opportunities to improve treatment up-front, devise drugs that target these resistant cells and prevent relapse from ever occurring.
“Our study has shown that genetic clones that contribute to disease recurrence already possess characteristics such as therapeutic tolerance that distinguish them from other clones at diagnosis,” says Dr. Stephanie Dobson, first author of the study who performed this research as a member of John Dick’s Lab. “Being able to isolate these clones at diagnosis, sometimes years prior to disease recurrence, has enabled us to begin to profile the properties allowing these particular cells to survive and act as reservoirs for relapse. This knowledge can be used to enhance our therapeutic approaches for targeting relapse and relapse-fated cells.”
“Xenografting added considerable new insight into the evolutionary fates and patterns of subclones obtained from diagnosis samples,” says John Dick, who is the co-senior author of the study, Senior Scientist at the Princess Margaret Cancer Centre and leader of OICR’s Acute Leukemia Translational Research Initiative. “We were able to gather extensive information about the genetics of the subclones from our models, which helped us describe the trajectories of each subclone and the order in which they acquired mutations.”
Ordering these mutations relied on the advanced machine learning algorithms designed by Dr. Quaid Morris and Jeff Wintersinger at the University of Toronto.
Research efforts are underway to build on these discoveries and determine how to block dRI clones.
The study was led by researchers at St. Jude Children’s Research Hospital, the Princess Margaret Cancer Centre and the University of Toronto and supported in part by OICR’s Acute Leukemia Translational Research Initiative.
This post has been adapted from the St. Jude Children’s Research Hospital news release.
September 30, 2019
McMaster University researcher and OICR Investigator, Dr. Kristin Hope, turns her stem cell discovery into a new treatment approach for leukemia.
A few years ago, Dr. Kristin Hope and her research team discovered a new way to grow rare life-saving blood stem cells. Now, the Hope Lab is using this discovery to suppress leukemic stem cells – the cells at the “root” of leukemia.
In their most recent study, published earlier this month in Cancer Research, the Hope Lab discovered that the same molecular pathway they found previously could be turned off to grow healthy stem cells could be turned on to impair the development of cancer stem cells.
The study suggests that this pathway, called the aryl hydrocarbon receptor (AHR) signaling pathway, could be leveraged as a potential therapeutic approach for acute myeloid leukemia – one of the most common subtypes of leukemia.
“We saw a loss of leukemic stem cells by activating – or turning on – the AHR pathway,” Hope says. “This brings us a step closer to a potential new therapy for patients with leukemia.”
The study group used a small molecule to activate the AHR pathway, finding that it had a significant effect in eliminating leukemic stem cells, but no effect on healthy cells. The group found similar results in cell cultures as well as in mice that were transplanted with human leukemia cells.
Hope, who is a Principal Investigator at McMaster University’s Stem Cell and Cancer Research Institute, will continue investigating this small molecule as a potential drug that could complement chemotherapies in the future.
“We will continue building on our understanding of the AHR pathway and how to control it,” she says. “This understanding will help us in the development of new therapies so that our discoveries can one day help patients.”
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.”
January 29, 2019
FACIT and Triphase Accelerator Announce New Partnership with Celgene for First-in-class WDR5 Leukemia Therapy
Largest transaction to date for Canadian-discovered preclinical asset arises from Ontario collaborators
TORONTO, ON (January 29, 2019) – Triphase Accelerator, together with its majority shareholder FACIT, today announced a new strategic collaboration with Celgene for a first-in-class preclinical therapeutic targeting the WDR5 protein for the treatment of blood cancers including leukemia. Triphase is a drug development company advancing novel compounds through Phase 2 proof-of-concept, including the WDR5 program.Continue reading – FACIT and Triphase Accelerator Announce New Partnership with Celgene for First-in-class WDR5 Leukemia Therapy
January 29, 2019
TORONTO (January 29, 2019) – A first-of-its-kind therapy for leukemia discovered by researchers in the Ontario Institute for Cancer Research’s (OICR) Drug Discovery Program, and under preclinical development, has attracted investment from Celgene Corporation that could exceed US$1 billion – which would make it the largest transaction to date for a preclinical asset discovered in Canada.
This investment will allow for clinical trials based in Ontario, and will further research and development of the drug and other cancer research innovations developed in the province. The commercialization of this technology was conducted by OICR’s strategic partner FACIT and demonstrates the realization of the two partners’ long-term vision of creating a sustainable pathway for therapeutic innovation in Ontario.
“The progress of this pre-clinical drug towards the clinic is an example of how OICR, working with its partners, is accelerating cancer research in Ontario and increasing investment so that new innovations can help patients as soon as possible,” says Dr. Laszlo Radvanyi, President and Scientific Director of OICR. “Today’s announcement shows how OICR and FACIT’s unique model for research and commercialization can generate long-term impact for the province of Ontario.”
The project is built on the observation that a protein known as MLL-1 plays an important role in promoting the development of leukemia. It does this through binding with a partner protein called WDR5. This new therapy works by disrupting the MLL-1/WDR5 protein-protein interaction, therefore inhibiting the cancer-promoting activity of the MLL-1 protein.
The possibility of targeting WDR5 to disrupt the cancer-driving activity of MLL-1 was first suggested by one of OICR’s partners, the Structural Genomics Consortium (SGC) at the University of Toronto, where researchers saw its potential and proposed a collaboration with OICR’s Drug Discovery (DD) program. OICR DD and SGC researchers worked together to develop an active and selective WDR5 “chemical probe” that could be used to test the anti-leukemia hypothesis. After OICR and SGC scientists demonstrated this probe could disrupt the interaction of WDR5 and MLL-1 in cells, they shared the compound with academic investigators in Ontario and around the world, who showed the probe could stop the growth of leukemia and other cancer cells.
Once the probe was in the public domain, the OICR DD group seized the opportunity to leverage its expertise to improve the drug-like properties and potency of the probe, while creating novel intellectual property, in order to fully realize its therapeutic and commercial potential. This subsequent development of the pre-clinical drug by OICR DD was made possible by their extensive experience in the pharmaceutical industry and academia, a unique model that has helped to develop assets that are solid candidates for investment and further development by industry partners. OICR DD is one of the only industry-academic hybrid drug discovery teams in Ontario.Continue reading – New potential treatment for leukemia discovered by OICR scientists draws major industry investment
September 10, 2018
Hamilton researchers discover that cancer stem cells may not be the only culprits of acute myeloid leukemia relapse
Although current chemotherapy for acute myeloid leukemia (AML) is effective in the short term, the disease often returns a few years after treatment. A new study suggests that the relapse of leukemia may not be caused by leukemic stem cells – a special set of cells that can avoid initial treatment by not dividing, then give rise to new cancerous cells after therapy – but rather a different class of leukemic cells.
July 10, 2018
Acute myeloid leukemia (AML) progresses quickly and requires treatment soon after diagnosis, but the disease begins long before becoming symptomatic. Early indicators of AML were thought to be indistinguishable from healthy aging. But now, an international group of researchers led in part by Dr. Sagi Abelson, a postdoctoral fellow in the lab of Dr. John Dick at the Princess Margaret Cancer Centre, has discovered distinctive traces of AML in patients up to 10 years before they were diagnosed with the disease.
October 20, 2017
Researchers have discovered a new potential treatment for acute myeloid leukemia (AML). They found that boosting fat cells (adipocytes) within bone marrow with the use of a common diabetes drug slowed the growth of cancerous cells and promoted the regeneration of healthy blood cells.
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.
December 7, 2016
Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and is one of the most deadly. Although AML is treated as a single disease, patient response to intensive curative-intent chemotherapy varies. It is currently difficult to predict who will do well with standard treatment, and who will not benefit from standard treatment and might do better enrolling in a clinical trial where they may be offered novel therapies.