Redefining blood cell development
Research by Society-funded Dr John Dick’s team at the Princess Margaret Cancer Centre could provide clues to how blood cancers develop.
The blood is constantly renewing itself, generating new blood cells to replace old or damaged ones. Understanding how the body produces more than 10 different types of blood cells is key to understanding what goes wrong in blood cancers and other disorders.
The classic view is that blood stem cells produce a series of intermediate cells that gradually specialize in a stepwise process to serve different functions. Paradigm-shifting research by Dr John Dick and his team at the Princess Margaret Cancer Centre, however, has now redefined this process.
By developing new ways to study single stem cells, they showed that specialized blood cells develop much more rapidly from stem cells than previously thought. This new discovery could allow researchers to learn more about how different blood cancers develop, identifying new opportunities for personalized treatment.
The full text of this work, published online in the journal Science in November, is available here.
How do mutations affect gene activity patterns in cancer?
New computational tool developed by Society-funded Dr Sohrab Shah (shown here with student Jiarui Ding (left)) will help zero in on new targets for personalized cancer therapy.
Cancer develops as a result of a stepwise accumulation of gene mutations that allow cells to grow out of control. Advances in DNA sequencing technology have allowed researchers to detect all of the gene mutations in an individual tumour. However, to develop effective personalized treatments, they need to know which mutated cancer genes are the best to target.
To this end, researchers need to understand how each mutation affects cancer cells. However, they currently have few tools to do this. So far, computer models have focused mainly on the DNA sequence itself. Dr Sohrab Shah, a scientist at the BC Cancer Agency, believes that there is much more to the story and that researchers need to simultaneously analyze which genes are mutated and the functional consequences of these mutations.
With support from a Canadian Cancer Society Innovation Grant, Dr Shah and his team developed a new mathematical model and computational tool to analyze how gene mutations affected gene expression patterns in thousands of tumours from 12 different cancer types. They identified over 100 new suspected cancer genes and several mutations whose effects were similar across many cancer types. These findings will help prioritize the selection of genes for further study as new therapeutic targets to advance personalized medicine in cancer.
"Our new method helps to determine which mutations in cancer cells are altering biological activity,” says Dr Shah. “This work provides a path forward for integrated analysis of mutations and gene expression to further our understanding of biological processes gone awry in cancer and to improve the potential of identifying the most important mutations for personalized, targeted therapy."
The full text of this work, published online in the journal Nature Communications in October, is available here.
Accelerating the development of a new prostate cancer treatment
A new collaboration will advance a prostate cancer therapeutic developed by Society-funded Dr Robert Day toward the clinic.
The increasing burden of prostate cancer is a challenge that must be met with renewed efforts to prevent it, increase survival rates and improve the quality of life for men living with this disease. A new collaboration between the Institut de pharmacologie de Sherbrooke (IPS) and the Centre for Drug Research and Development (CDRD) is poised to make an impact by bringing a new prostate cancer treatment developed by Dr Robert Day closer to the clinic.
Prostate cancer is the third leading cause of death from cancer in men in Canada and is projected to be the most commonly diagnosed cancer by 2030. While hormone therapy is often effective in early stages, many prostate tumours develop resistance within a few years. Innovative, new treatments are therefore needed.
With the support of a Canadian Cancer Society Impact Grant, Dr Robert Day has been taking an outside-the-box approach to developing a new prostate cancer therapy. Dr Day, a researcher at the IPS at the Université de Sherbrooke, led pioneering work to establish the PACE4 enzyme as a promising therapeutic target in prostate cancer.
“Before our work began, the idea of targeting PACE4 to treat cancer was not well understood, nor was it on anyone’s radar. Since then, our work has provided the proof-of-concept that inhibition of PACE4 blocks cancer growth through a fundamentally new approach,” Dr Day explains.
Dr Day and his team designed and developed an inhibitor of PACE4 that was both potent and stable when injected into mice. In mice with growing prostate tumours, the PACE4 inhibitor shrunk the tumour size by 60% in under 3 weeks, compared to controls.
The collaboration with the CDRD, Canada’s national drug development and commercialization centre, will advance the clinical testing and commercialization of this new candidate therapeutic. The first step is to develop a formulation of the PACE4 inhibitor that is stable in the human body and can be administered in a more convenient pill form. Additional studies will establish its safety and side effect profile.
“We’re very excited to see this new treatment approach taking steps toward the clinic,” says Dr Day, “If successful, this collaboration could be a great example of how results from the lab can translate effectively to improved patient care.”
Connecting with the cancer research community at the CCRC
Researchers from across Canada and beyond connected at the 2015 Canadian Cancer Research Conference in Montreal.
The 2015 Canadian Cancer Research Conference (CCRC)
was held November 8th to 10th in Montreal. This conference, which occurs every 2 years, brings together the Canadian cancer research community spanning the entire research spectrum, from cancer prevention to end-of-life care and from basic discovery research through translation to clinical practice and policy.
The Canadian Cancer Society was a major supporter of the conference and many Society-funded researchers contributed to the high caliber scientific program. Attendees learned about recent advances in areas as varied as immunotherapy, cancer prevention and global cancer control, and personalized medicine, among others. Many Society staff from across the country attended the conference and acted as ambassadors to share information about our mission, research programs at the Canadian Cancer Society Research Institute (CCSRI) and our publications at an information booth located in the poster exhibition hall.
CCSRI also played a key role in satellite meetings and workshops designed to complement and build on the CCRC experience. CCSRI partnered with the Canadian Institutes of Health Research’s Institute of Cancer Research (CIHR-ICR) to host a satellite meeting for new faculty and senior postdoctoral fellows to provide strategic education and mentoring opportunities for the next generation of great cancer researchers. Following the conference, the Society’s Prevention Network
also held a full-day workshop entitled “Cancer Prevention: Science and Society” to define strategic prevention priorities and explore opportunities for interdisciplinary collaboration from research, policy and program perspectives.
We look forward to the next CCRC in 2017!
Studying leukemia from different angles
Society-funded researcher Dr Guy Sauvageau studied 2 important forms of acute myelogenous leukemia (AML) in Montreal.
Acute myelogenous leukemia (AML) can be found in several forms with different molecular features and patient outcomes. Learning more about the molecular characteristics of AML can improve diagnosis, prognosis and therapy for this blood cancer. Dr Guy Sauvageau, director of the Molecular Genetics of Stem Cells research unit and a principle investigator at the Institute for Research in Immunology and Cancer (IRIC), led a study of 2 forms of AML characterized by abnormalities in the MLL gene that often have poor outcomes.
By sequencing DNA from AML cells and measuring gene activity, the researchers – for the first time – identified a pattern of gene activity shared by these 2 AML subsets. They also tested how the cells responded to multiple anticancer drugs and found a subset of AMLs whose mutations made it particularly susceptible to certain combination treatments. The wealth of information gathered about gene activity in AML should improve how it is diagnosed and how treatments can be tailored to improve survival.
The full text of this work, published online in August in the journal Nature Genetics, is available here
Modelling drug responses of human lung cancers in mice
Society-funded researcher Dr Ming-Sound Tsao (shown here with co-authors Erin Stewart (left) and Dr Frances Shepherd (right)) uses mice to realistically model human lung cancers and their response to drugs at the Princess Margaret Cancer Centre.
The growth of many non–small cell lung cancers (NSCLCs) can be driven by a mutated version of EGFR, a protein that signals cells to multiply. Several available drugs targeting EGFR are used to treat lung cancer, including afatinib (Giotrif), erlotinib (Tarceva) and gefitinib (Iressa). While many individuals initially respond to these drugs, almost all of them eventually develop resistance and their disease progresses.
To test new lung cancer treatments and identify biomarkers to predict who is most likely to respond to them, researchers need experimental models that realistically mimic human lung cancer so they can study it in the lab. One type of model relies on implanting fresh tissue from human lung tumours into mice. These are called patient-derived xenografts, meaning a graft (or implant) of tissue from a different species (human into mouse). While these models can be difficult to develop, they offer great opportunities for researchers to study the biology, response to therapy and mechanisms of drug resistance in human lung cancer.
Supported by the Society, Dr Ming-Sound Tsao, a Senior Scientist at the Princess Margaret Cancer Centre in Toronto, is studying how the molecular features of early stage NSCLCs can be exploited to improve treatment and survival. Dr Tsao and his team successfully generated mouse xenograft models from 6 different tumours from people with NSCLC that had EGFR mutations. The mouse models accurately mimicked the appearance and molecular features of each person’s original tumour. They also had variable responses to drugs blocking EGFR that closely mirrored how the corresponding tumour behaved in the human body. In one case, where the person’s lung tumour was resistant to therapy, the researchers were able to identify molecular features that made the lung cancer dramatically susceptible to an alternative therapeutic approach in the mouse.
These mouse models can be used not only to understand what makes each person’s lung cancer grow, but also to identify new opportunities for targeted, more personalized treatment. “Mouse models derived from patient tumours may speed up the development of new cancer drugs and improve patient selection for emerging molecularly targeted treatments,” comments Dr Tsao.
This research was supported by 3 grants from CCSRI to Dr Tsao, including the Rachelle Archambault Innovation Grant.
The full text of this work, published online in June in the Journal of Clinical Oncology, is available here
Current Oncology calls for papers on health economics in cancer
Submit papers on Canadian cancer costing research for a special issue of Current Oncology by September 30, 2015.
The journal Current Oncology will be publishing a special supplemental issue on "Original Canadian cancer costing research". This supplement will be co-edited by Dr Nicole Mittmann (Cancer Care Ontario, Toronto, Ontario) and Dr Claire de Oliveira (Centre for Addiction and Mental Health, Toronto, Ontario).
Current Oncology is a peer-reviewed journal that focuses on Canadian oncology practice and studies of international significance. Researchers are encouraged to submit appropriate manuscripts by September 30, 2015.
The full details and submission instructions can be found here
A new ultrasensitive blood test for cancer biomarkers
Innovative method to detect cancer mutations developed by Society-funded researcher Dr Shana Kelley at the University of Toronto.
New methods to recognize molecules in the blood that reliably detect cancers and track how they respond to treatment could change the way cancers are diagnosed and managed. Tumours can shed molecules into the bloodstream that carry information about mutations found in the cancer cells, which researchers are studying for their potential as cancer biomarkers. These approaches have advantages over traditional biopsies that can be invasive to patients and challenging for some cancers that are not readily accessible in the body.
Dr Shana Kelley and her group developed a new, extremely sensitive test that uses sensors on a chip to detect cancer mutations in blood samples. They used their new chip to detect key cancer-driving gene mutations in blood samples from people with lung or skin cancers. While the underlying technology is complex, the non-invasive test was simple to perform, fast (as short as 5 minutes) and could be automated to keep costs low. They are developing this technology to be used in the clinic as an alternative to tissue biopsies to detect cancer, monitor how each patient responds to therapy and tailor treatment decisions.
“Our chip-based approach to detecting cell-free nucleic acids provides a straightforward and sensitive way to look for tumour-related sequences using non-invasive sampling,” says Dr Kelley, “and we are excited about its application to the further development of liquid biopsy-based patient monitoring.”
The full text of this significant research, published online in June in the journal Nature Chemistry, is available here
Society-funded cancer researchers appointed to Order of Canada
Drs Janet Rossant, Mary Gospodarowicz, James Rutka and Martin Yaffe received prestigious national honours on Canada Day
On July 1, 2015, Drs Janet Rossant, Mary Gospodarowicz, James Rutka and Martin Yaffe were among 100 individuals appointed to the Order of Canada, one of the highest civilian honours in the country. The Order recognizes 3 tiers of recipients – Companions, Officers and Members – for outstanding achievement, dedication to the community and service to the nation.
Dr Rossant, Chief of Research Emeritus at The Hospital for Sick Children (SickKids) and Professor at the University of Toronto, was appointed Companion of the Order of Canada (the highest tier) for her outstanding contributions to developmental and stem cell biology and her national and international scientific leadership.
Dr Gospodarowicz, Medical Director at the Princess Margaret Cancer Centre and Professor at the University of Toronto and Dr Rutka, Neurosurgeon and Senior Scientist at SickKids and Professor at the University of Toronto were appointed Officers of the Order of Canada. Dr Gospodarowicz was recognized for her contributions to improving cancer radiotherapy and her leadership in advancing cancer care worldwide.
Dr Rutka was honored for his role in advancing the treatment of brain cancer in children and his international leadership in neurosurgery.
Dr Martin Yaffe, Senior Scientist at the Sunnybrook Research Institute and Professor at the University of Toronto, was appointed Member of the Order of Canada for his scientific breakthroughs in breast cancer screening and his commitment to improving women’s health.
All 4 recipients have been supported by Society funding and we have been fortunate to have partnered with them. We congratulate all recipients on their great achievements!
Understanding molecular variation within each prostate tumour
Dr Robert Bristow at the Princess Margaret Cancer Centre breaks ground on understanding molecular differences between distinct regions in prostate tumours.
Not all prostate cancers behave the same, even when the tumours have similar clinical features. One possible explanation for this tumour-to-tumour variability is that each tumour contains a unique molecular makeup. Dr Robert Bristow – recipient of a Canadian Cancer Society Research Scientist Award – and a team from the Canadian Prostate Cancer Genome Network studied DNA from prostate tumours from several men, examining multiple distinct regions to create “portraits” for each sample. They found many differences in the genetic abnormalities present in each region of each single tumour. They also discovered a new role for the MYCL1 gene in prostate cancer. “The ability to understand the unique genetics of each tumour within a man’s prostate gland means that we can now understand the big picture of the cancer,” comments Dr Bristow. This may provide important information for tailoring treatment to each individual as personalized medicine.
The full text of this important research, published in the journal Nature Genetics, is available here: http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.3315.html
Examining the link between breast stem cells, aging and cancer
Society-funded research by Dr Rama Khokha at the Princess Margaret Cancer Centre used a mouse model to study how stem cells impact aging breast tissue.
Given that age is the primary risk factor for breast cancer in women, it is important to understand what occurs during aging that contributes to cancer development. It has been suggested that stem cells ultimately lose their capacity to regenerate tissue with age, resulting in the degeneration of aging tissue. Dr Rama Khokha and her group made an important link between stem cells, aging and breast cancer. Published in the journal Nature Cell Biology, Dr Hartland Jackson from the Khokha lab discovered a set of genes that increase the number of stem cells in the mammary (breast) tissue of old mice, preserving the tissue's health. Contrary to the current belief that more stem cells increase cancer risk, the extended breast tissue lifespan in this study was not associated with an increase in breast cancer induced by a chemical. "Understanding how stem cells maintain our tissues is important for the prevention of all diseases associated with aging, including cancer," says Dr Khokha. These findings suggest an opportunity to harness a biological process to curtail aging and benefit stem cell therapy for tissue regeneration, without altering cancer susceptibility.
This study was supported through the former Canadian Breast Cancer Research Alliance.
The full text of this important research, published in the journal Nature Cell Biology, is available here: http://www.nature.com/ncb/journal/v17/n3/full/ncb3118.html
Hookah use among youth in Canada is increasing in popularity
Society-funded research by Dr Steve Manske at the Propel Centre for Population Health Impact found that hookah use among high school students is a growing concern.
Cigarette smoking is decreasing in North America, but there is an increased consumption of alternate tobacco products. One alternative, shisha tobacco, is conventionally smoked through a water pipe, also known as a hookah. A hookah is a traditional Middle Eastern pipe, but is becoming more prevalent among youth and young adults across the world. Studying data from the national 2012-2013 Youth Smoking Survey, Dr Steve Manske and his group at the Propel Centre for Population Health Impact described the prevalence of use and perceptions of the safety of hookah smoking among Canadian grade 9-12 students. They found that about one in twenty students reported currently using hookah, and that use has increased since 2010. They also discovered that among hookah users, flavored tobacco was a popular choice. Equally concerning was that over a third of students believed that hookah smoking was less harmful than cigarettes, and those with that opinion had a much greater likelihood of using a hookah. These findings highlight the need for better surveillance of hookah use, in addition to traditional cigarettes, and can be used to inform policy on tobacco control.
The full text of this important research, published in the journal Cancer Causes and Control, is available here
Dr Janet Rossant receives latest Canada Gairdner Award
SickKids Chief of Research Dr Janet Rossant named the recipient of 2015 Canada Gairdner Wightman Award.
The Canadian Cancer Society is thrilled to congratulate Dr Janet Rossant on receiving the 2015 Canada Gairdner Wightman Award. Dr Rossant, Chief of Research and Senior Scientist at The Hospital for Sick Children and Professor at the University of Toronto, is being recognized for her outstanding scientific contributions to developmental biology and stem cell research, and her national leadership in advancing research programs aimed at improving children’s health. This award is given to a Canadian scientist who has demonstrated outstanding leadership in medicine and medical science. Dr Rossant is an internationally recognized scientist who has made significant contributions to the understanding of stem cells, paving the way for novel therapies against several diseases, including cancer. She has also held many vital leadership roles in the scientific community, including President of the International Society for Stem Cell Research, Deputy Scientific Director of the Canadian Stem Cell Network, and Director of the Ontario Institute for Regenerative Medicine. The Society has been proud to support Dr Rossant’s research and fortunate to benefit from her years of service on grant review panels.
Research suggests a new treatment option for prostate cancer
Society-funded research by Dr Robert Day at Université de Sherbrooke has identified PACE4 as a therapeutic target for prostate cancer.
One of the first Impact grants ever awarded is paying dividends. While blocking the male hormone, androgen, is effective in the early stages of prostate cancer, it eventually fails after 2-3 years. With an Impact grant, Dr Robert Day and his team at Université de Sherbrooke are developing a new therapeutic approach from a completely separate angle, by targeting the growth of cancer cells through the enzyme PACE4. In the journal Oncotarget, they provided the first proof of concept that blocking PACE4 stops prostate cancer progression in mice. This significant finding could lead to a new therapeutic strategy for prostate cancer.
The full text of this important research, published in the journal Oncotarget, is available here: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=2918&path%5B%5D=6327
Risk assessment for hereditary stomach cancer
Society-funded research by Dr David Huntsman at BC Cancer Agency has generated reliable estimates for stomach cancer risk in CDH1 mutation carriers.
A rare but aggressive form of stomach cancer is often difficult to detect early enough to provide effective therapy. While it is known to be hereditary, accurate risk assessments for individuals with particular gene mutations are lacking. Dr David Huntsman’s group sought to help people who carry a particular gene mutation understand what their individual risks are of developing hereditary stomach cancer. By analyzing the genetics of nearly 4,000 individuals from 75 families who have a history of this cancer, they determined that men and women who carry mutations in the CDH1 gene have a 70% and 56% chance of developing stomach cancer, respectively. They also identified a number of other genetic mutations that may increase one’s risk, but more work needs to be done to calculate the risk they pose. These findings will have immediate influence on clinical care – when to start screening, how often to be screened and whether to undergo preventive surgery.
The full text of this important research, published in the journal JAMA Oncology, is available here: http://oncology.jamanetwork.com/article.aspx?articleid=2108851