“As sequencing technologies become more affordable and accessible, they are revolutionizing how physicians monitor and treat cancer,” says Dr. Dennis Kim, a clinical researcher and leukemia specialist at University Health Network’s Princess Margaret Cancer Centre.
Dr. Kim is bringing this idea to practice. He recently led a study to explore the use of next-generation sequencing—the newest and fastest DNA sequencing technologies—to monitor the treatment of acute myeloid leukemia, the most common type of leukemia in adults.
The study findings describe a sequencing approach that can be used to identify leukemia patients who are at risk for relapse after they receive bone marrow transplants—and does so better than current approaches.
“Because leukemia occurs in the blood, getting a biopsy can be as convenient and simple as taking a blood sample. This is one reason why sequencing technology is particularly applicable to this disease,” says Dr. Zhaolei Zhang, one of the key collaborators on this study, and a Professor at the Donnelly Centre for Cellular and Biomolecular Research at the University of Toronto.
In the study, the team screened the genetic sequences of over 100 individuals with acute myeloid leukemia for mutations that are known to be involved in the disease. They did this at multiple points along the cancer journey: at initial diagnosis, before treatment, and at 21, 90 and 180 days after bone marrow transplant. They also collected samples yearly thereafter and at relapse.
While previous studies have shown that certain mutations can help predict whether the cancer will relapse, this is the first study to monitor mutations using next-generation sequencing before and after treatment.
“In mapping how these mutations change with treatment, we found that 21 days after bone marrow transplant treatment is a clinically important time point. That’s because patients that we identified as ‘high risk’ using our sequencing approach relapsed soon after,” says Dr. Kim.
“At this time point, our approach could be used to identify which patients would most likely benefit from more timely and aggressive complementary chemotherapy in order to prevent relapse.”
This work was supported by the National Research Foundation of Korea, the Korean Ministry of Health & Welfare, the Natural Science and Engineering Council, the National Natural Science Foundation of China, the Leukemia and Lymphoma Society of Canada and The Princess Margaret Cancer Foundation.
Kim T, Moon JH, Ahn JS, Kim YK, Lee SS, Ahn SY, Jung SH, Yang DH, Lee JJ, Choi SH, Lee JY, Tyndel MS, Shin MG, Lee YJ, Sohn SK, Park SK, Zhang Z, Kim HJ, Kim DDH. Next-generation sequencing based post-transplant monitoring of acute myeloid leukemia. Blood. 2018 Aug 14. pii: blood-2018-04-848028. doi:10.1182/blood-2018-04-848028.
UHN researchers received two of the four major research awards from the Canadian Cancer Society.
Dr. Pamela Ohashi was honoured with the 2018 Robert L. Noble Prize, which is presented to an individual for outstanding achievement in basic biomedical research. Dr. Ohashi is considered one of the world’s foremost leaders in advancing tumour immunotherapies and was recognized by the Society for her research into strategies to promote the immune system’s ability to fight cancer.
Drs. Gelareh Zadeh and Rodger Tiedemann were the co-recipients of the 2018 William E. Rawls Prize, which is awarded to exemplary young investigators who are making important contributions to cancer control.
Dr. Zadeh is UHN’s Head of Surgical Oncology and is an internationally recognized brain cancer researcher. Her high impact publications have garnered significant attention and have broken new ground in our understanding of the genetics of difficult-to-treat cancers.
Dr. Tiedemann is a highly respected hematologist and expert in multiple myeloma—a cancer of immune cells in the blood. His research examines genetic changes that occur in drug-resistant tumour cells in multiple myeloma.
Other UHN researchers that have previously received these prestigious awards from the Canadian Cancer Society include Drs. Rama Khokha, Mitsu Ikura, Brian Wilson, John Dick and Tak Mak (Robert L. Noble Prize); and Drs. Philippe Bedard, Camilla Zimmermann and Geoffrey Liu (William E. Rawls Prize).
Congratulations to Drs. Ohashi, Zadeh and Tiedemann!
On September 12 2018, Dr. Philippe Monnier was named the inaugural recipient of the Restore Vision 20/20 Award by the Foundation Fighting Blindness. He is a Senior Scientist at the Krembil Research Institute and an Associate Professor at the University of Toronto.
The Restore Vision 20/20 Award aims to support the best science that has a clear path to becoming an innovative, sight-restoring treatment for retinitis pigmentosa within the next five years. Retinitis pigmentosa refers to a family of genetic disorders that damage light-sensitive cells in the retina, leading to gradual vision loss over time. It is one of the most common inherited diseases of the retina, affecting around 1 in 4000 Canadians. To date, there are no treatments available in Canada for the disease.
The Award was given to Dr. Monnier to support his research developing a new experimental drug that promotes the survival of light-sensing cells in the retina. The drug could potentially restore vision not only in retinitis pigmentosa, but in other retinal eye diseases, such as age-related macular degeneration and glaucoma.
The Foundation Fighting Blindness is a Canadian charitable organization that leads the fight against blindness by advancing retinal disease research, education and public awareness. Since 1974, the Foundation has invested $30 million to support vision research across Canada.
Genetic discoveries have made huge strides in recent decades. These advances and new technologies are revolutionizing our access to genetic testing. Some companies offer “at-home” genetic tests that make it as simple as sending in a mouth swab to the company. Accredited labs also offer tests for specific genes believed to be linked to various diseases.
These tests can provide insight into your risk for certain diseases. However, not all genes cause disease, and care must be taken when creating a screening test for a given gene. Clinicians who are not experts in genetics or a particular disease may also place undue faith in lab tests: they may assume that because a lab is offering testing for a specific gene, it must be linked to a disease.
An international team led by Toronto General Hospital Research Institute Scientist and Peter Munk Research Chair in Cardiovascular Molecular Medicine Dr. Michael Gollob recently used an evidence-based framework to investigate the appropriateness of genetic tests. The team focused on genetic tests used for Brugada syndrome—a rare heart rhythm disease that puts around one in 2000 people at risk for sudden cardiac death.
For the study, the researchers included a group of 21 genes for Brugada Syndrome that are currently tested by labs in the United States and internationally. Three teams independently reviewed each gene to determine whether sufficient evidence exists to link them with Brugada syndrome.
Only one gene, known as SCN5A, was definitively linked to Brugada syndrome—while evidence was lacking for the other 20 genes. All three teams independently agreed on these results.
These results are troubling because they reveal that many genetic tests may fail to provide real insights. Use of these dubious tests could lead to incorrect diagnostic conclusions, unnecessary testing, treatments and anxiety and stress for patients and families.
As to why the laboratories offer so many unproven tests, Dr. Gollob remarks that “Laboratories do not have to justify the inclusion of genes for clinical testing. It’s possible that the increasingly competitive marketplace and a ‘more is better’ mentality has led to rapidly expanding gene panels. Our findings indicate that more rigorous standards are required to ensure that genetic tests are meaningful.”
This work was supported by the US National Human Genome Research Institute. Dr. Gollob is supported by a Peter Munk Research Chair in Cardiovascular Medicine from the Toronto General & Western Hospital Foundation.
Hosseini SM, Kim R, Udupa S, Costain G, Jobling R, Liston E, Jamal SM, Szybowska M, Morel CF, Bowdin S, Garcia J, Care M, Sturm AC, Novelli V, Ackerman MJ, Ware JS, Hershberger RE, Wilde AAM, Gollob MH (Chair); NIH-Clinical Genome Resource Consortium. Reappraisal of Reported Genes for Sudden Arrhythmic Death: An Evidence-Based Evaluation of Gene Validity for Brugada Syndrome. Circulation. 2018 Jun 29. pii: CIRCULATIONAHA.118.035070. doi:10.1161/CIRCULATIONAHA.118.035070.
The role of insulin in improving the ability of the immune system to fight infection has been described for the first time by Toronto General Hospital Research Institute (TGHRI) scientists.
The research findings were published in Cell Metabolism by first author Dr. Sue Tsai, postdoctoral fellow, and senior authors, Dr. Daniel Winer, TGHRI Scientist and Anatomical Pathologist at University Health Network; and Dr. Shawn Winer, Anatomical Pathologist at St. Michael's Hospital.
A fast and effective immune response protects us against infections, such as influenza. T cells are at the heart of this process: they divide rapidly and secrete chemical messenger proteins (cytokines) that direct the rest of the immune system to destroy the virus.
A lot of work has been done on insulin’s role in regulating blood sugar and how the body turns it into energy, yet little is known about how it affects the immune system.
The research team designed T cells that could no longer respond to insulin. They then observed what happened to the T cells after they exposed them to a flu virus.
They discovered that insulin gives the immune system the boost needed to fight the infection. Without it, the T cells were unable to effectively destroy the virus.
"T cells are at the heart of so many diseases," says Dr. Tsai, "Understanding them at the cellular level will give us the best opportunity to discover new pathways to target for new therapies." In the future, she says, we could harness this insulin signalling pathway to either boost the immune response to create vaccines, for example, or dampen it to heal inflammatory illnesses such as arthritis, ulcerative colitis and Crohn's disease.
Tsai S, Clemente-Casares X, Zhou AC, Lei H, Ahn JJ, Chan YT, Choi O, Luck H, Woo M, Dunn SE, Engleman EG, Watts TH, Winer S, Winer DA. Insulin Receptor-Mediated Stimulation Boosts T Cell Immunity during Inflammation and Infection. Cell Metab. 2018 Aug 22. pii: S1550-4131(18)30504-7. doi:10.1016/j.cmet.2018.08.003.
This work was supported by the Canadian Institutes of Health Research, Diabetes Canada, the J.P. Bickell Foundation Grant, the Banting and Best Diabetes Centre at the University of Toronto, and the Toronto General & Western Hospital Foundation. D Winer holds a Tier 2 Canada Research Chair in Immunometabolism. M Woo holds a Tier 2 Canada Research Chair in Signal Transduction in Diabetes Pathogenesis.
A University Health Network spin-off company known as Acumyn Inc. was recently acquired by global radiotherapy giant Elekta.
Acumyn was created by UHN’s Technology Development and Commercialization (TDC) office to commercialize AQUATM, a software platform developed at Princess Margaret by a team led by Dr. Daniel Letourneau. The clinical software platform brings all the demanding quality assurance tests and calibrations a radiotherapy clinic needs to perform into a single place, helping to manage and automate these complex tasks.
AQUA helps manage department workload and scheduling, reduces the likelihood of machine down-time and patient delays, and makes it easier to maintain regulatory compliance, while saving time. “There was a clear need to better manage quality assurance activities in the radiation therapy clinic, and we saw that this was a gap in the broader market,” says Dr. Daniel Letourneau, Associate Head, Medical Physics at Princess Margaret, and Co-Founder and CTO at Acumyn.
“[AQUA is] a global commercial success that came from the need to assure Princess Margaret cancer patients get the safest, highest level of care possible,” says Dr. David Jaffray, Director of the Techna Institute, Executive Vice-President of Technology and Innovation at UHN, and Acumyn Co-Founder.
Techna used its medical device engineering and product development expertise to help Acumyn “productize” AQUA. Techna’s services included project management; documentation to achieve ISO 13485 and 9001 certification; the creation of marketing materials, a user manual and website; user interface design; and financial services. Techna’s professional services provided the expertise needed to advance the software platform without requiring the small Ontario-based start-up to hire full-time employees for every role. This expertise, combined with real-world evidence and product refining provided by Princess Margaret and the support of TDC, helped Acumyn to scale-up and succeed. “TDC took the calculated risk, formed the UHN start-up and afforded the CEO the requisite business and financial support so that the value created in the company could be captured optimally,” underlines Mark Taylor, TDC’s Team Lead.
With this multi-million-dollar acquisition, Elekta plans to integrate AQUA more broadly across its portfolio while further developing its quality assurance offering through the expertise that the Acumyn team brings with it. “This will accelerate the uptake of safe radiotherapy worldwide,” concludes Dr. Mary Gospodarowicz, Medical Director of the Princess Margaret Cancer Centre. Adds John Reid, Director of TDC at UHN, “Acumyn’s success story is an example of UHN’s ability to discover, develop and deliver commercially interesting research, which not only attracts top investors and management teams, but also enriches the Toronto ecosystem.”
