Cancer is a genetic disease—one that results from changes, known as mutations, to our DNA and genes.
When it comes to promoting cancer, not all mutations are equal. This is because cancer causing mutations affect certain genes far more frequently than others. One of these genes is known as MYC, which codes for the MYC protein. Over half of all cancers show changes to levels of MYC—a distinction that has led to it being referred to as one of the ‘hallmarks of cancer’.
Because MYC is involved in so many different cancers, targeting it would be a promising strategy to stop the growth of cancer. However, to date, and despite extensive efforts, drugs developed to block MYC have failed in experimental models.
New findings by Dr. Linda Penn, a Senior Scientist at the Princess Margaret (PM) Cancer Centre, have overcome this hurdle. Her latest work, published in Cancer Cell, reveals a new way to target MYC —one that is based on new insights into how the MYC protein functions in the cell.
Along with her collaborators, Dr. Penn’s team identified a protein—known as G9a, a histone H3K9-methyltransferase complex—that binds to and works together with the MYC protein to promote the growth of cancer.
“By identifying that MYC that binds to G9a to repress the expression of specific genes, we have overcome a long-standing mystery in the field and identified a potential new anticancer target,” says Dr. Penn.
“Importantly, we were able to show in various experimental and preclinical models that targeting G9a slows MYC-driven tumour growth. This is a major advancement because MYC has been declared ‘undruggable’ using traditional drug development approaches. Our work suggests that, by targeting a key partner protein of MYC, anticancer drugs for MYC-driven cancers could be developed.”
This work was supported by the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research, the Terry Fox Research Institute and The Princess Margaret Cancer Foundation. LZ Penn holds a Tier 1 Canada Research Chair in Molecular Oncology. C Arrowsmith holds a Tier 1 Canada Research Chair in Structural Proteomics.
Tu WB, Shiah YJ, Lourenco C, Mullen PJ, Dingar D, Redel C, Tamachi A, Ba-Alawi W, Aman A, Al-Awar R, Cescon DW, Haibe-Kains B, Arrowsmith CH, Raught B, Boutros PC, Penn LZ. MYC Interacts with the G9a Histone Methyltransferase to Drive Transcriptional Repression and Tumorigenesis. Cancer Cell. 2018 Oct 8;34(4):579-595.e8. doi: 10.1016/j.ccell.2018.09.001.
Dr. Paaladinesh Thavendiranathan and his colleagues at Toronto General Hospital Research Institute and Mount Sinai Hospital recently reported that pregnant women who have previously received treatment for cancer are at an increased risk for heart disease.
During pregnancy, the heart needs to work harder to satisfy the increased day-to-day demands of the body. Women with reduced heart function are at an increased risk of heart failure during pregnancy. Cancer can also increase the risk of heart disease.
“Many drugs used for chemotherapy cause damage to the heart, which may lead to conditions such as coronary heart disease and congestive heart failure,” explains Dr. Thavendiranathan. “Some radiation therapy can also be tough on the heart. Many cancer survivors recover from such heart damage with time, others don’t and may not even be aware of it.”
The research team found that women who did not experience heart damage from cancer treatment are at a very low risk of developing heart failure during pregnancy; women who did have heart damage from cancer treatment have approximately 1 in 3 chance of developing heart failure during pregnancy.
This new study addresses gaps in previous works by specifically and methodically following cancer survivors through pre- and post-pregnancy assessments in a dedicated high risk pregnancy program at Mount Sinai Hospital lead by Dr. Cynthia Maxwell. The study also provides information to help doctors provide pre-conception counselling.
“Women with a history of heart problems related to cancer treatment—even if they have recovered—should have a cardiologist as part of their care if they are pregnant,” recommends Dr. Thavendiranathan. “They should receive close monitoring during pregnancy at a centre with expertise in cardiac disease in pregnancy.”
One such centre is the Peter Munk Cardiac Center at the University Health Network, which has an established program in Pregnancy and Heart Disease lead by Dr. Candice Silversides.
“If you have a history of heart damage and are thinking about pregnancy, talk to your doctor about your risk of heart disease during pre-conception counselling,” urges Dr. Thavendiranathan. “The heart is unlikely to fail if abnormalities are discovered early and managed properly.”
This work was supported by the Canadian Institutes of Health Research and the Toronto General & Western Hospital Foundation.
Liu S, Aghel N, Belford L, Silversides CK, Nolan M, Amir E, Maxwell C, Thavendiranathan P. Cardiac Outcomes in Pregnant Women With Treated Cancer. J Am Coll Cardiol. 2018 Oct. https://doi.org/10.1016/j.jacc.2018.07.085.
On October 4, Evotec AG and MaRS Innovation announced that they had chosen to support a drug discovery project led by Dr. Jeremy Sivak through their LAB150 partnership. This highly competitive investment is the second of its kind to be awarded in Canada and the first to a University Health Network (UHN) team.
The UHN Office of Research Trainees (ORT) is proud to announce the release of the latest issue of The ORT Times!
The ORT Times is UHN's monthly trainee-focused newsletter. It highlights news and editorials about trainee life, articles to help developing researchers get the most out of their training experience at UHN, tips on career development, and research training opportunities within and outside of UHN.
● Welcome to UHN
● UHN’s 2018 Vanier Scholars
● 2018 Postdoc Appreciation Week
● MBP Summer Student Poster Day
● ORT Travel Awards
● OSOTF Graduate Fellowship
Conference Reports: Read conference reports from Gah-Jone, Muammar, Lisa and Arvind.
Read and download the full issue now!
To see past issues of The ORT Times, please visit ORT’s website here.
“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.