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  • One in two Canadians will get cancer, but research offers hope for cures

    by TFRI Admin | Jun 22, 2017

    Terry Fox

    Close to 50 per cent of all Canadians will be diagnosed with cancer in their lifetime. One in four Canadians will die of the disease. Around 60 per cent of high-priority cancer research projects were not funded in 2016.

    These sobering statistics were released by the Canadian Cancer Society on June 20 – but there’s good news too: survival rates have increased from 25 per cent in the 1940s to 60 percent today, a number both the Terry Fox Research Institute and the Terry Fox Foundation are determined to keep improving by investing in top-tier cancer research across the country and internationally.

    There has been tremendous success in increasing five-year survival rates for some cancers, such as thyroid (98%), testicular (96%), prostate (95%), melanoma (88%), female breast (87%) and Hodgkin lymphoma (85%). However survival rates for some cancers have remained stubbornly low, such as pancreatic (8%), lung and bronchus (17%), liver (19%), and brain (24%). These are the areas we are focusing on to find cures for all cancers.

    In 2016, the Terry Fox Research Institute and the Terry Fox Foundation invested $22.9 million dollars into research projects across the country with a focus on hard-to-treat cancers. These include: 

    Terry’s dream was to fund research to cure cancer, and he inspired us with that dream. We believe that it is through research that cures to cancer will be found, and survival rates for even the most challenging cancers will continue to increase.

  • TFRI's Dr. Victor Ling recognized for breakthrough in fighting drug-resistant cancers

    by TFRI Admin | May 29, 2017

    Dr. Victor Ling, president and scientific director of The Terry Fox Research Institute, has been recognized by The Vancouver Sun for his breakthrough in fighting drug-resistant cancers. 

    An authority on multi-drug resistance in cancer, Dr. Ling is well-known for his discovery of p-glycoprotein, the first molecule identified to be responsible for drug resistance. 

    The Vancouver Sun is counting down to Canada's 150th birthday by profiling 150 remarkable British Columbians. To read the full article on Dr. Ling click here.

  • MATE2 expression a negative predictive biomarker to metformin’s efficacy in cancer treatment, study suggests

    by TFRI Admin | May 24, 2017

    The drug metformin is typically used to treat Type 2 diabetes, and some cancer patients have shown improved outcome when given the drug. A recent study by TFRI’s hypoxia group sheds new light on biomarkers that may indicate the drug’s efficacy in patients.

    Metformin inhibits mitochondrial function inside cells, thereby reducing oxygen consumption and interfering with cell proliferation. The team examined its effects on oxygen consumption, cell growth, and the expression of organic cation transporters (OCTs) and multi-drug and toxin extrusion transporters (MATEs) in a panel of 19 cancer cell lines. The expression of these transporters is known to mediate the anti-diabetic effects of metformin, but they have not been extensively studied in cancerous cell or tissues. The group sought to determine their potential roles as predictive biomarkers.

    Published in PLOS ONE in December 2016, study results showed that all cancer cells are susceptible to the inhibition of oxygen consumption by metformin, which increases the radiotherapy response by reducing hypoxic tumour fractions. However, results suggested MATE2 expression might result in resistance to the anti-proliferative (prevention of growth) effect of metformin and should be considered as a negative predictive biomarker in clinical trials.

    Interestingly, the anti-proliferative response of different cell lines had high variability and some cell lines were very resistant. Notably HNC (head and neck cancer) cell lines were most resistant while the prostate cancer LNCaP cell line was most sensitive. Also sensitive was the lung carcinoma line A549.

    The study also showed that when mice with A549 tumours were given anti-diabetic doses of metformin it resulted in intra-tumoral accumulation of metformin and reduced hypoxic tumour fractions.

    The team’s previous research showed patients respond poorly to treatment if their tumours are low in oxygen, a state known as ‘hypoxia’. These tumours are more likely to grow and spread aggressively, whereas reduced oxygen consumption often leads to improved tumour oxygenation and radiation response.

    The team is currently running a clinical trial assessing the benefit of metformin in patients with cervix cancer, and are exploring whether tumor expression of OCTs and MATEs can serve as predictive biomarkers for the benefit of metformin. 

    Study: MATE2 Expression is Associated with Cancer Cell Response to Metformin

    Authors: Sanjana Chowdhury, Eric Yung, Melania Pintilie, Hala Muaddi, Selim Chaib, ManTek Yeung, Manlio Fusciello, Jenna Sykes, Bethany Pitcher, Anna Hagenkort, Trevor McKee, Ravi Vellanki, Eric Chen, Robert G. Bristow, Bradly G. Wouters, Marianne Koritzinsky.

    Funding: This work was financially supported in part by the Terry Fox Research Institute (New Frontiers Research Program PPG14-1036; to M.K, R.G.B and B.G.W).

    Chart info (Chart F on 8/18 of article)
    Figure 1

    The chart above: The AUC* was normalized across the cell panel and is shown after arranging cell lines in order of increased resistance (*area under-dose response curve).

    TFRI Links, Spring 2017

     

  • Groundbreaking study sheds light on signaling molecules that control human hematopoietic stem cell survival and growth

    by TFRI Admin | May 24, 2017

    diagram for TFRI May 2 2017TFRI’s long-funded program project on human leukemia has made groundbreaking progress in the quest to expand human blood stem cells for therapeutic purposes. The team’s paper published in Blood (January 2017) reports the first use of a new technology to discover how growth factors activate signaling molecules inside these very rare human cells to control their survival, ability to divide and retention of their “stemness” properties.

    Growth factor combinations that would promote an expansion of human blood-forming stem cells (HSCs) outside of the body have been sought for many years by investigators around the world, but with limited success. One problem may be the historical assumption that the ability of blood stem cells to stay alive, divide and maintain their “stemness” would all be activated by the same mechanisms upon growth factor stimulation. This team has now shown this assumption is incorrect and have further demonstrated how different growth factors activate different mechanisms to produce different effects, which then must be co-ordinated to actually elicit all three desired effects (cells stay alive, divide to generate two daughter stem cells).

    These studies were made possible through the use of a relatively new technology called mass cytometry. This technology that allows dozens of different types of molecules present inside cells (as well as on their cell surface) to be measured simultaneously, one cell at a time, even when they represent less than 0.1 per cent of all the cells being analyzed.

    Specifically, the team found that growth factor-activated AKT and ß-catenin in human blood-forming stem cells are required to promote their survival and division. This information allowed the team to identify new agents that may be used to enhance or replace certain growth factors.

    Expanding human blood stem cells for therapeutic purposes is one of the major goals of research in the blood-forming system and understanding how this process works is also fundamental to understanding how it goes wrong in human leukemia. This paper exemplifies the importance of developing, adapting and combining new technologies to gain insights into what makes important, but extremely rare, cells function properly.  

    Two of the paper’s principal authors, Drs. Connie Eaves and Keith Humphries, based at the BC Cancer Agency in Vancouver, have led one of the longest-running research programs funded by the Terry Fox Foundation. Previous stages of the program created the genetic tools to modify normal blood-forming stem cells so that they mimic leukemia cells, while the latest stage of the program uses those tools to create reproducible models of different types of different types of human leukemia. 

    Study: Distinct signaling programs control human hematopoietic stem cell survival and proliferation

    Authors: David J. H. F. Knapp, Colin A. Hammond, Nima Aghaeepour, Paul H. Miller, Davide Pellacani, Philip A. Beer, Karen Sachs,Wenlian Qiao, WeiJia Wang, R. Keith Humphries, Guy Sauvageau, Peter W. Zandstra, Sean C. Bendall, Garry P. Nolan, Carl Hansen, and Connie J. Eaves.

    Funding: This work was supported in part by a Terry Fox Foundation New Frontiers Program Project Grant

    TFRI Links, Spring 2017

  • Novel 17-gene test predicts if patients with aggressive leukemia will respond to treatment or not

    by TFRI Admin | May 24, 2017

    2016-12-06-stanley-ng-lead
    Researcher Stanley Ng holds up a cartridge used to measure the gene expression levels of cancer cells. (Photo: University of Toronto). 


    What if there was a way to predict if leukemia patients would respond to standard treatment or not? A TFRI-funded team has developed a novel, 17-gene signature test from leukemia stem cells (LSCs) that determines just that.

    The test provides doctors with a risk scoring tool that can predict within just a day or two of diagnosis an acute myeloid leukemia (AML) patient’s treatment response, as well as aid clinicians in treatment decisions. The work was published in Nature (December 2016, first author Stanley Ng). 

    Patients predicted not to benefit from standard treatment could be guided to novel clinical therapies and/or post-remission strategies, according to the study’s lead investigator Dr. Jean Wang at Princess Margaret (PM) in Toronto.   

    AML is the deadliest form of leukemia, with low cure rates especially in older patients. Although many patients respond to initial therapy, disease recurrence is common and difficult to treat. The high rate of relapse in AML has been attributed to the persistence of LSCs, which possess numerous stem cell properties connected with treatment resistance.

    The new biomarker, named the LSC17 score, is a signature of 17 genes that are specific to LSCs. To create it, the team first generated a list of genes differentially expressed between 138 LSC+ and 89 LSC− cell fractions derived from 78 AML patient samples. They then performed a sparse regression analysis of LSC gene expression against survival in a large training cohort.

    Calculating a patient’s score is simple: the patient’s blood or bone marrow sample is tested to measure the expression levels of the 17 genes. Those with a higher LSC17 score have the greatest risk of death if treated with standard chemotherapy, knowledge that could guide clinicians to offer them alternative options such as a clinical trial.

    Dr. John Dick, who leads TFRI’s prolific cancer stem cell program, was one of the co-senior authors of the team. Besides AML, Dr. Dick is also investigating the role of cancer stem cells in glioblastoma and multiple myeloma, two deadly and incurable cancers.


    Study:
     A 17-gene stemness score for rapid determination of risk in acute leukemia

    Authors: Stanley W. K. Ng, Amanda Mitchell, James A. Kennedy, Weihsu C. Chen, Jessica McLeod, Narmin Ibrahimova, Andrea Arruda, Andreea Popescu, Vikas Gupta, Aaron D. Schimmer, Andre C. Schuh, Karen W. Yee, Lars Bullinger, Tobias Herold, Dennis Görlich, Thomas Büchner, Wolfgang Hiddemann, Wolfgang E. Berdel, Bernhard Wörmann, Meyling Cheok, Claude Preudhomme, Hervé Dombret, Klaus Metzeler, Christian Buske, Bob Löwenberg, Peter J. M. Valk, Peter W. Zandstra, Mark D. Minden, John E. Dick & Jean C. Y. Wang.

    Funding: This work was supported in part by the Terry Fox Foundation.

    TFRI Links, Spring 2017

  • Canadian study identifies predictive genomic signature for high-risk prostate cancer

    by TFRI Admin | May 24, 2017

    Prostate cancer

    Understanding why some prostate cancer tumours are indolent while others eventually kill patients is the focus of many within the global cancer research community. A top Canadian research team has provided new answers with the potential to change the way aggressive tumours are treated and, importantly, improve cure rates.

    The study was conducted by a TFRI and Prostate Cancer Canada funded research team led by Drs. Robert Bristow (Princess Margaret Cancer Centre) and Paul Boutros (Ontario Institute for Cancer Research), and was published in Nature in January 2017. 

    The team revealed for first time that the complexity of the prostate genome can be used to predict whether patients with localized and non-indolent prostate cancers will have more or less aggressive cancers. Improving this understanding could allow researchers to figure out how to deploy existing therapies more precisely; for example, triaging treatment based on defined prostate cancer subtypes. Further, it may provide novel candidate targets for creating new intensified therapies to increase cures in those patients at greatest risk of death.

    Prostate cancer remains the most frequently diagnosed non-skin cancer in Canadian men, and its incidence continues to grow as the population ages. Around 30 per cent of men relapse despite successful initial treatment, and current clinical prognostics cannot explain why. To counter this, the team took a novel approach to the analysis in the present study: rather than focusing on small subsets of the genome, information present in all of the DNA was used to come up with a predictive signature that accurately describes the complexity of prostate cancers. The signature comprises numerous molecular aberrations that outperformed well-described prognostic biomarkers for the disease.

    Two hundred whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumours with similar clinical risk profiles were examined.  Numerous molecular aberrations that indicated disease recurrence were identified and could be used in determining disease prognosis. Further, local hypermutation events that correlated with specific genomic profiles often occurred.

    The research team defined 40 properties of prostate cancers, including mutation density, presence/absence of chromothripsis and kataegis and a series of recurrent somatic mutations. The team’s data also highlights the differences in mutational profiles between localized intermediate risk cancers and metastatic castrate resistant prostate cancer.

    The present study furthers the ability to understand why some prostate cancers are aggressive, and despite the best available treatments may go on to kill the patient, while others are adequately treated by precision radiotherapy or surgery alone. Besides furthering the field of precision medicine and potentially changing the way aggressive prostate cancers are treated, this data will also serve as a major genomic resource for groups around the world.

    Study: Genomic hallmarks of localized, non-indolent prostate cancer

    Authors: Michael Fraser, Veronica Y. Sabelnykova, Takafumi N. Yamaguchi, Lawrence E. Heisler, Julie Livingstone, Vincent Huang, Yu-Jia Shiah, Fouad Yousif, Xihui Lin, Andre P. Masella, Natalie S. Fox, Michael Xie, Stephenie D. Prokopec, Alejandro Berlin, Emilie Lalonde, Musaddeque Ahmed, Dominique Trudel, Xuemei Luo, Timothy A. Beck, Alice Meng, Junyan Zhang, Alister D’Costa, Robert E. Denroche, Haiying Kong, Shadrielle Melijah G. Espirit, Melvin L. K. Chua, Ada Wong, Taryne Chong, Michelle Sam, Jeremy Johns, Lee Timms, Nicholas B. Buchner, Michèle Orain, Valérie Picard, Helène Hovington, Alexander Murison, Ken Kron, Nicholas J. Harding, Christine P’ng, Kathleen E. Houlahan, Kenneth C. Chu, Bryan Lo, Francis Nguyen, Constance H. Li, Ren X. Sun, Richard de Borja, Christopher I. Cooper, Julia F. Hopkins, Shaylan K. Govind, Clement Fung, Daryl Waggott, Jeffrey Gree, Syed Haider, Michelle A. Chan-Seng-Yue, Esther Jung, Zhiyuan Wang, Alain Bergeron, Alan Dal Pra, Louis Lacombe, Colin C. Collins, Cenk Sahinalp, Mathieu Lupien, Neil E. Fleshner, Housheng H. He1, Yves Fradet, Bernard Tetu, Theodorus van der Kwast, John D. McPherson, Robert G. Bristow & Paul C. Boutros.

    Funding: P.C.B. was supported by a Terry Fox Research Institute New Investigator Award and a CIHR New Investigator Award. D.T. was part of the Terry Fox Foundation Strategic Health Research Training Program in Cancer Research at the Canadian Institute of Health Research and Ontario Institute for Cancer Research.

    TFRI Links, Spring 2017

  • Complement inhibitors decrease neutralization of some oncolytic viruses, increase treatment efficacy

    by TFRI Admin | May 24, 2017

    iStock-621842166

    The use of oncolytic viruses to stimulate a patient’s immune system as well as directly kill tumour cells is a novel approach to eradicating cancer, but antibodies that permanently inactivate the virus are often generated that counter treatment efficacy. An Ottawa-based lab has come up with a way of countering this problem by using a complement inhibitor that prevents the virus’ neutralization, thereby ensuring viral vectors reach their target.

    Multiple doses of oncolytic viruses are likely needed to maximize the therapeutic effect, however the delivery of the latter doses is limited by the presence of anti-viral antibodies both in the blood as well as in the tumor microenvironment.

    The present study published in Molecular Therapy – Oncolytics (November 2016) shows that the antibodies that are generated against the lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP), while non-neutralizing on their own, can mediate virus neutralization in a complement-dependent manner. An oncolytic virus that was pseudotyped with this glycoprotein was neutralized by immune serum with intact complement, whereas neutralization was prevented when a complement inhibitor was present.

    This discovery has had immediate benefit to patients: by using a transient complement inhibitor oncolytic viruses pseudotyped with the LCMV glycoprotein can be effectively delivered to a tumour without being neutralized by antibodies for a period of time, thus increasing its efficacy. For example, virus stability in the blood of immunized animals increased by approximately 100-fold when a complement was inhibited, leading to a corresponding increase in viral titer in the tumour.

    The present study also shed light on using animal models in oncolytic virus research. The antibody response to LCMV has been studied primarily in mouse models, and it was thought that the antibodies that were generated against the virus were essentially biologically inert. However, mouse complement does not fully recapitulate the effects of human complement. The team more accurately modelled the effect of complement by using rats instead of mice, and it became clear that the anti-LCMV GP antibodies induced profound complement-mediated neutralization. This finding underscores that mouse models have important limitations that must be recognized when designing translational therapeutic approaches.

    Study: Complement inhibition enables tumour delivery of LCMV glycoprotein pseudotyped viruses in the presence of antiviral antibodies

    Authors: Laura Evgin, Carolina S Ilkow, Marie-Claude Bourgeois-Daigneault, Christiano Tanese de Souza, Lawton Stubbert, Michael S Huh,Victoria A Jennings, Monique Marguerie, Sergio A Acuna, Brian A Keller, Charles Lefebvre, Theresa Falls, Fabrice Le Boeuf, Rebecca A Auer, John D Lambris, J Andrea McCart, David F Stojdl and John C Bell.

    Funding: J.C.B. is supported by the Terry Fox Research Institute, the Ontario Institute for Cancer Research, and the Ottawa Regional Cancer Foundation.

    TFRI Links, Spring 2017
  • B.C. team study detects rare ovarian cancer mutation in ctDNA of patients

    by TFRI Admin | May 18, 2017


    #6


    A study examining the circulating tumour DNA (ctDNA) of women with a rare ovarian cancer has been successful in detecting the mutation which is the defining feature of adult granulosa cell tumours (AGCTs) in the plasma of patients.

    The finding by a B.C. team studying rare and forme fruste tumours is important in that it may help to identify women at risk of relapse for the disease, as well as to provide a non-invasive way to monitor patients in follow-up. Their work was published in the Journal of Molecular Diagnostics (January 2017).

    FOXL2 402C>G (C134W) is the pathognomonic mutation found in these ovarian tumours, which affect three to five per cent of women diagnosed with the disease. AGCT is typically slow-growing and indolent, with a 97 per cent, five-year disease-specific survival rate for the majority of women with early Stage I tumours. However, disease recurrence occurs in 30 per cent of women within four to 10 years, and 50 to 70 per cent of this cohort will eventually die of the disease. Identifying ways to prevent relapse and improve monitoring for relapse will improve outcomes for these patients.

    The team (led by Dr. David Huntsman) developed a specific digital droplet PCR (ddPCR) assay to apply to circulating cell-free DNA extracted from 120 serial plasma samples of 35 patients from Helsinki, Finland and Vancouver. FOXL2 ctDNA mutations were detected in the plasma of 12 of 33 AGCT patients (36 per cent) with both primary (35 per cent) and recurrent tumours (19 per cent). The ctDNA mutation was detected in four patients without clinical disease, of which one relapsed during follow-up.

    Tumour size was identified as a factor in determining ctDNA mutation positivity and the team noted that tumour size was significantly smaller in the ctDNA mutation-negative cases. The team made recommendations for future studies pertaining to the amount of plasma needed and its isolation upon collection of the patient blood samples to ensure the quality of the cell-free DNA and to increase the yield of the ctDNA, thereby increasing the sensitivity and clinical applicability of the assay.

    The present study (first author Anniina Färkkilä) not only offers a non-invasive method of detecting AGCT via liquid biopsies, but may also be able to detect recurrence before the onset of clinical symptoms or elevation of serum marker levels. Ideally, this method could indicate the presence of low-level metastatic tumour cells and highlight patients at increased risk for relapse.

    Study: FOXL2 402C>G Mutation Can Be Identified in the Circulating Tumor DNA of Patients with Adult-Type Granulosa Cell Tumor

    Authors: Anniina Färkkilä, Melissa K. McConechy, Winnie Yang, Aline Talhouk, Ying Ng, Amy Lum, Ryan D. Morin, Kevin Bushell, Annika Riska, Jessica N. McAlpine, C. Blake Gilks Leila Unkila-Kallio, Mikko Anttonen, and David G. Huntsman.

    Funding: Supported by grants including the Terry Fox Research Institute grant 1021 (The Terry Fox New Frontiers Program Project grant in the Genomics of Forme Fruste Tumors: New Vistas on Cancer Biology and Treatment) (M.K.M.)

    TFRI Links, Spring 2017
  • Terry Fox Foundation is media outlet’s top pick for donating to cancer research

    by TFRI Admin | May 17, 2017

    Terry FoxAn article published in The National Post in mid-May has identified the Terry Fox Foundation as one of the best places to donate to cancer research in Canada.

    “Some charities, such as the Terry Fox Foundation, direct the vast majority of their spending to cancer research. Others spend little, even nothing, on research at all,” writes reporter Claire Brownell.

    The article, part of the newspaper’s multi-part series New War on Cancer, recommends donating to the Foundation.

    Around 84 per cent of all TFF funds go directly to cancer research – a percentage The National Post found to be significantly higher than the average charity.

    Read the full story here: http://news.nationalpost.com/features/the-fundraising-complex

  • Four 2017 New Investigator award recipients announced

    by TFRI Editor | Apr 25, 2017

    Awards to three New Investigators were made by TFRI in late December 2016, for a total investment of $1.3 million. A fourth New Investigator Award was also made possible through the generosity of a private donor to the Terry Fox Foundation, the late Gregory Hohn of Penticton, B.C. Each award is valued at $450,000 for a term of three years, commencing Jan. 1, 2017.

    Recipients are:

    • Dr. Housheng Hansen He, scientist, Princess Margaret, UHN, and assistant professor, University of Toronto Department of Medical Biophysics.  “Understanding the Function of Circular RNA in Tumour Hypoxia.” Mentoring program: TFRI PPG on “A Research Pipeline for Hypoxia-Directed Precision Cancer Medicine,” led by Drs. Rob Bristow and Bradly Wouters. 

    • Dr. Frédérick Mallette, assistant professor, Université de Montréal Department of Medicine/Maisonneuve-Rosemont Hospital Research Centre. “Deciphering the Oncogenic Properties of Cancer-Associated IDH1/2 Mutations.” Mentoring program: TFRI PPG in “Oncometabolism and the Molecular Pathways that Fuel Cancer,” led by Dr. Vincent Giguère.

    • Dr. Peter Stirling, scientist, Terry Fox Laboratory, BC Cancer Agency, and assistant professor, UBC Department of Medical Genetics.  “Functioning SWI/SNF Chromatin Remodeller Mutations in Rare and Common Tumours.” Mentoring program: TFRI PPG on “Genomics of Forme Fruste Tumours: New Vistas on Cancer Biology and Management,” led by Dr. David Huntsman.

    • Dr. Trevor Pugh, scientist, Princess Margaret, UHN, and assistant professor, University of Toronto. "Single Cell Dissection and Non-Invasive Monitoring of Childhood Cancer and Immune Systems During Treatment." Mentoring program: "Precision Oncology for Young People (PROFYLE)," led by Dr. David Malkin.

    TFRI has featured profiles on each recipient on our website.

    A total of 10 applications were received for the competition. Reviewers said all applicants prepared high-quality research proposals and the ranking of applicants was challenging.

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