May 6, 2020
OICR-supported study helps move promising CAR-T cell therapy into a first-in-child clinical trial
Recurrent brain tumours are some of the most difficult cancers to treat, with no approved targeted therapies available and only a few potential therapies in clinical trials. Developing new drug treatments for these tumours is challenging in part because the drugs must overcome the blood-brain barrier and specifically target cancer cells while sparing the surrounding critical regions of the brain. Scientists at The Hospital for Sick Children (SickKids) have discovered a new solution.
In a study, recently published in Nature Medicine, a SickKids-led research team describes a novel treatment approach that delivers chimeric antigen receptor T (CAR-T) cell therapy directly into the cerebrospinal fluid that surrounds the tumour. Their findings show that the approach was effective in treating ependymoma and medulloblastoma, two common types of brain tumours, in experimental mouse models of human disease.
“The vast majority of children with recurrent metastatic medulloblastoma or ependymoma currently have a deadly prognosis, so it is very exciting to think we have identified a novel approach to treat this underserved patient population,” says senior author Dr. Michael Taylor, Neurosurgeon, Senior Scientist in the Developmental and Stem Cell Biology program and Garron Family Chair in Cancer Research at SickKids and Co-lead of OICR’s Brain Cancer Translational Research Initiative.
CAR-T cell therapies, which use genetically engineered immune cells to attack cancer cells, are remarkably effective in treating certain types of lymphomas and leukemias. Whereas CAR-T therapies are typically delivered through the blood stream, the research team discovered that delivering their engineered T cells directly into the cerebrospinal fluid provided a better chance for the therapy to reach and eliminate brain tumours.
The team performed in-depth molecular studies to design CAR-T cells that can recognize specific molecules on the surface of brain tumour cells. They also found that the use of a complementary approved cancer medication, azactyidine, boosts the efficacy of their approach.
Now, building on these findings, collaborators at Texas Children’s Hospital have launched a first-in-child clinical trial to test the safety and anti-tumour efficacy of their new strategy.
“This work was possible thanks to the concerted collaboration of our Pediatric Cancer Dream Team, which brought together scientists studying tumor genomics and tumor immunotherapy around the world to enable the design of more effective therapies for children with incurable and hard to treat cancers,” says corresponding author Dr. Nabil Ahmed, associate professor of pediatrics and immunology, section of hematology-oncology at Baylor and Texas Children’s Hospital.
This research was supported in part by OICR through OICR’s Brain Cancer Translational Research Intitiative and funding provided to the Stand Up to Cancer (SU2C) Canada Cancer Stem Cell Dream Team.
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.
February 25, 2020
Researchers discover that childhood brain cancer could be treated by blocking key cell-surface protein, pointing to a potential treatment approach with fewer toxic side effects
Chemotherapy for children with brain cancer is often toxic, leaving patients with serious life-long side effects but OICR-funded researchers have uncovered a new approach that may help.
In a study published in the Journal of Experimental Medicine, the Ontario-based research team discovered that blocking a specific protein on the surface of brain cancer cells can suppress the rampant growth of a tumour without harming the development of the brain.
The study focused on the protein CLIC1 in medulloblastoma, the most common type of childhood brain cancer. The group found that disrupting CLIC1 can halt medulloblastoma growth with very little effect on the developing brain in mice.
“Brain cancer is the leading cause of cancer-related death in children and young adults,” says Dr. Xi Huang, Scientist in the Developmental & Stem Cell Biology Program at The Hospital for Sick Children (SickKids) and senior author of the study. “We need new treatments to help these patients.”
We believe our findings are significant because ion channels have been successfully targeted to treat numerous human diseases.Michelle Francisco
CLIC1 belongs to a class of proteins called ion channels, which are important in the development of several other diseases like diabetes, epilepsy and high blood pressure. Many existing drugs and compounds act as ion channel modulators. The Huang Lab now has the high-throughput screening equipment to assess thousands of drug-like chemicals for those that can best block these ion channels.
“We believe our findings are significant because ion channels have been successfully targeted to treat numerous human diseases,” says Michelle Francisco, Research Project Coordinator in the Developmental & Stem Cell Biology Program at SickKids and first author of the study. “This helps pave the way between this discovery today and the impact it can have in the clinic.”
These findings build on Huang’s previous research on the potassium channel EAG2, which – like CLIC1 – is critical to medulloblastoma growth. In partnership with collaborators, Huang has shown that EAG2 could be blocked with an FDA-approved drug for schizophrenia to treat medulloblastoma in experimental mouse models and in a small patient study.
“We are fortunate to work with world-leading brain cancer researchers in Ontario,” Huang says, “We look forward to continuing our research to find new solutions for this devastating disease by targeting ion channels.”
This research was funded by OICR’s Brain Cancer Translational Research Initiative, SickKids Foundation, Arthur and Sonia Labatt Brain Tumour Research Centre, Garron Family Cancer Centre, b.r.a.i.n.child, Meagan’s Walk, Natural Sciences and Engineering Research Council (NSERC) Discovery Grant, U.S. Department of Defense (DoD) Peer Reviewed Cancer Research Program Career Development Award, Canadian Institute of Health Research (CIHR) Project Grants, and Sontag Foundation Distinguished Scientist Award to Xi Huang.
October 9, 2019
Change in just one letter of DNA code in a gene conserved through generations of evolution can cause multiple types of cancer
Toronto – (October 9, 2019) An Ontario-led research group has discovered a novel cancer-driving mutation in the vast non-coding regions of the human cancer genome, also known as the “dark matter” of human cancer DNA.
The mutation, as described in two related studies published in Nature on October 9, 2019, represents a new potential therapeutic target for several types of cancer including brain, liver and blood cancer. This target could be used to develop novel treatments for patients with these difficult-to-treat diseases.
“Non-coding DNA, which makes up 98 per cent of the genome, is notoriously difficult to study and is often overlooked since it does not code for proteins,” says Dr. Lincoln Stein, co-lead of the studies and Head of Adaptive Oncology at the Ontario Institute for Cancer Research (OICR). “By carefully analyzing these regions, we have discovered a change in one letter of the DNA code that can drive multiple types of cancer. In turn, we’ve found a new cancer mechanism that we can target to tackle the disease.”Continue reading – Researchers discover a new cancer-driving mutation in the “dark matter” of the cancer genome
July 17, 2019
Collaborative research group maps the three-dimensional genomic structure of glioblastoma and discovers a new therapeutic strategy to eliminate cells at the roots of these brain tumours
Current treatment for glioblastoma – the most common type of malignant brain cancer in adults – is often palliative, but new research approaches have pointed to new promising therapeutic strategies.
A collaborative study, recently published in Genome Research, has mapped the three-dimensional configuration of the genome in glioblastoma and discovered a new way to target glioblastoma stem cells – the self-renewing cells that are thought to be the root cause of tumour recurrence.
The research group integrated three-dimensional genome maps of glioblastoma with other chromatin and transcriptional datasets to describe the mechanisms regulating gene expression and detail the mechanisms that are specific to glioblastoma stem cells. They are one of the first groups in the world to perform three-dimensional genomic analyses in patient-derived tumour samples.
“The 3D configuration of the genome has garnered much attention over the last decade as a complex, dynamic and crucial feature of gene regulation,” says Dr. Mathieu Lupien, Senior Scientist at the Princess Margaret Cancer Centre, OICR Investigator and co-author of the study. “Looking at how the genome is folded and sets contacts between regions tens to thousands of kilobases apart allowed us to find a new way to potentially tackle glioblastoma.”
Through their study, the group discovered that CD276 – a gene which is normally involved with repressing immune responses – has a very important role in maintaining stem-cell-like properties in glioblastoma stem cells. Further, they showed that targeting CD276 may be an effective new strategy to kill cancer stem cells in these tumours.
Lupien adds that advancements in three-dimensional genomics can only be made through collaborative efforts, like this initiative, which was enabled by OICR through Stand Up 2 Cancer Canada Cancer Stem Cell Dream Team, OICR’s Brain Cancer Translational Research Initiative and other funding initiatives.
“This research was fueled by an impressive community of scientists in the area who are committed to finding new solutions for patients with brain cancer,” Lupien says. “Our findings have emphasized the significance of three-dimensional architectures in genomic studies and the need to further develop related methodologies to make sense of this intricacies.”
Senior author of the study, Dr. Marco Gallo will continue to investigate CD276 as a potential therapeutic target for glioblastoma. He plans to further delineate the architecture of these cancer stem cells to identify more new strategies to tackle brain tumours.
“A key problem with current glioblastoma treatments is that they mostly kill proliferating cells, whereas we know that glioblastoma stem cells are slow-cycling, or dormant. Markers like CD276 can potentially be targeted with immunotherapy approaches, which could be an effective way of killing cancer stem cells, irrespective of how slowly they proliferate,” says Gallo, who is an Assistant Professor at the University of Calgary. “Being able to kill cancer stem cells in glioblastoma could have strong implications for our ability to prevent relapses.”
May 1, 2019
Study identifies earliest traces of brain cancer long before the disease becomes symptomatic
Toronto (May 1, 2019) – Brain tumours are the leading cause of non-accidental death in children in Canada, but little is known about when these tumours form or how they develop. Researchers have recently identified the cells that are thought to give rise to certain brain tumours in children and discovered that these cells first appear in the embryonic stage of a mammal’s development – far earlier than they had expected.
“Progress in the development of more effective brain cancer treatments has been hampered in large part by the complex heterogeneity – or the variety of cells – within each tumour,” says Dr. Michael Taylor, Paediatric Neurosurgeon and Senior Scientist in Developmental and Stem Cell Biology at The Hospital for Sick Children (SickKids) and co-lead of the study. “We recognized that new technologies could allow us to unravel some of this complexity, so we combined our expertise with McGill and OICR to approach this problem together.”
Using mouse models, the research group investigated the different types of normal brain cells and how they developed at various timepoints in the cerebellum of the brain – the most common location for childhood brain tumours to appear. They mapped the lineages of over 30 types of cells and identified normal cells that would later transform into cancerous cells, also known as the cells of origin.
To pinpoint these specific cells, the group relied on single cell sequencing technology, which allows researchers to look at individual cells more clearly than traditional sequencing methods.
In their investigation, the cells of origin were observed much earlier in fetal development than one would expect, says Taylor, who is also a Professor in the Departments of Surgery and Laboratory Medicine and Pathology at the University of Toronto and Co-lead of OICR’s Brain Cancer Translational Research Initiative.
“Our data show that in some cases, these tumours arise from cell populations and events that would occur in humans at six weeks in utero,” says Dr. Lincoln Stein, Head of Adaptive Oncology at OICR and co-lead of the study. “This means that the brain tumours may be starting long before they show in clinic, even before a woman may know she is pregnant.”
“The brain is extraordinarily complex. These findings are not only important for better understanding brain tumours but they will also allow us to learn more about these cells and how they work, in order to help children with neurodevelopmental delays. What we have accomplished as a team in this study brings hope for patients,” adds Dr. Nada Jabado, Paediatric Hemato-Oncologist and Senior Scientist in the Child Health and Human Development Program at the Research Institute of the McGill University Health Centre and co-lead of the study. Dr. Jabado is also a professor of Pediatrics and Human genetics at McGill University.
“If we can understand where these tumours originate, we can better understand which cells to target and when to target them to create more effective and less toxic therapies for children,” says Ibrahim El-Hamamy, PhD candidate at OICR and co-first author of the study. “We’ve found new avenues and opportunities in a very complex disease and we look forward to actualizing this potential.”
With this knowledge, researchers can now study the differences between the development of normal, healthy cells and the cells that will eventually give rise to cancerous cells.Continue reading – The unanticipated early origins of childhood brain cancer
August 16, 2018
Ottawa researchers discover a new way to make cancer cells more susceptible to virus-based therapies
Over the past decade, researchers have made significant progress in designing oncolytic viruses (OVs) – viruses that destroy cancer cells while leaving healthy tissue unharmed. However, some cancer cells are resistant to this type of therapy and their resistance mechanisms remain poorly understood.
Researchers at the The Ottawa Hospital and University of Ottawa, under the leadership of Dr. Carolina Ilkow, have discovered that a common cellular mechanism, RNAi, allows cancer cells to fight back against cancer-fighting viruses. Their findings, recently published in the Journal for Immunotherapy of Cancer, show that blocking RNAi processes in tumours can make cancer cells more susceptible to OVs.
May 17, 2018
Combination of erectile dysfunction drugs and flu vaccine may help kill remaining cancer after surgery
A remarkable study led by Dr. Rebecca Auer from The Ottawa Hospital (TOH) shows that the unlikely combination of erectile dysfunction drugs and the flu vaccine may boost the immune system’s ability to clean up cancer cells left behind after surgery. This method demonstrated promising results in a mouse model, where it reduced the spread of cancer following surgery by 90 per cent. Now the approach will be tested in a first-of-its-kind clinical trial involving 24 patients at TOH.
March 8, 2018
OICR’s Brain Cancer Translational Research Initiative (TRI) and the Terry Fox Precision Oncology for Young People Program (PROFYLE) are partnering to share data and deliver improved treatment options to young brain cancer patients.
January 30, 2018
Early results from COMPASS trial demonstrate benefits of using genomic sequencing to guide treatment for pancreatic cancer
Genomic profiling has allowed physicians to customize treatments for patients with many types of cancer, but bringing this technology to bear against advanced pancreatic cancer has proven to be extremely difficult. OICR’s pancreatic cancer Translational Research Initiative, called PanCuRx, has been conducting a first-of-its-kind clinical trial called COMPASS to evaluate the feasibility of using real time genomic sequencing in pancreatic cancer care. The research team recently reported early results from the trial, which show how they overcame the challenges of genomic profiling specific to pancreatic cancer and gained new insights about the disease.
PanCuRx is focused on improving treatment for pancreatic adenocarcinoma (PDAC), the most common form of pancreatic cancer and the fourth leading cause of cancer death in Canada. The group’s approach centres around understanding the genetics and biology of PDAC to inform the selection of therapies, as well as the development of new treatments.
January 4, 2018
Researchers at The Ottawa Hospital and the University of Ottawa have found that a combination of two immunotherapies – oncolytic viruses and checkpoint inhibitors – was successful in treating triple-negative breast cancer in mouse models. Triple-negative breast cancer is the most aggressive and hard-to-treat form of 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.