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  • Subtype-specific alterations in BCL2 linked to poor post-treatment outcomes in non-Hodgkin lymphoma

    by TFRI Admin | Sep 06, 2017


    TFRI funding for researchers at the Centre for Lymphoid Cancer (BC Cancer Agency) has resulted in the discovery that subtype-specific alterations in a driver gene for non-Hodgkin lymphoma (BCL2) is strongly associated with poor patient outcomes after treatment.

    The work by Drs. David Scott, Randy Gascoyne, Joseph Connors, and Christian Steidl was published in Blood (May 2017). Diffuse large B-cell lymphoma (DLBLC) is the most common type of non-Hodgkin lymphoma, predominantly affecting people in their mid-60s. BCL2 and MYC are critical driver genes for the disease and play key roles in in normal B-cell differentiation and tumourigenesis.

    Genetic alterations in both genes were profiled in the present study via next-generation sequencing and high-resolution SNP array in 347 de novo DLBCL patients that had already been treated with R-CHOP, the standard chemotherapy treatment for this disease. The team discovered the clinical impact of genetic aberrations in DLBLC needs to be placed in the context of the cell-of-origin molecular subtype and, when this is done, subtype-specific alterations in BCL2 are revealed as being strongly associated with poor outcomes post treatment.

    Further, this work showed that the incidence of MYC/BCL2 genetic alterations and their clinical significance were mainly dependent on cell-of-origin (COO) subtypes. There are two main subtypes of DLBLC based on COO, activated B-cell-like (ABC) subtype and the germinal center B-cell-like (GCB) subtype, both of which have different biology and clinical behaviour. In ABC and GCB subtypes, gain of BCL2 and translocation of BCL2 respectively often led to poor outcomes. The results suggest that COO subtype-specific biomarkers based on these BCL2 genetic alterations can be effectively used to risk-stratify patients with DLBCL treated with immunochemotherapy.

    This paper highlights the value of examining clinical correlates in large homogeneously treated population registry-based cohorts. The finding that BCL2 dysregulation is a common feature of patients with inferior survival will prioritize examination of therapeutic approaches that target BCL2, and hopefully result in better patient outcomes in the future.

    Study: Genetic profiling of MYC and BCL2 in diffuse large B-cell lymphoma determines cell-of-origin–specific clinical impact

    Authors: Daisuke Ennishi, Anja Mottok, Susana Ben-Neriah, Hennady P. Shulha, Pedro Farinha, Fong Chun Chan, Barbara Meissner, Merrill Boyle, Christoffer Hother, Robert Kridel, Daniel Lai, Saeed Saberi, Ali Bashashati, Sohrab P. Shah, Ryan D. Morin, Marco A. Marra, Kerry J. Savage, Laurie H. Sehn, Christian Steidl, Joseph M. Connors, Randy D. Gascoyne, and David W. Scott.

    Funding: This study was supported by a Program Project Grant from the Terry Fox Research Institute (Grant No. 1023 to R.D.G.)

    TFRI LINKS, Summer 2017
  • Discovery of seven new ovarian cancer subtypes opens door for more targeted treatments

    by TFRI Admin | Sep 06, 2017

    Dr. Shah

    The discovery of seven new genetic subtypes of ovarian cancer may lead to targeted treatments for women diagnosed with this disease, including those with the most malignant form and those who do not respond well to current chemotherapy treatments.

    The findings by a group of TFRI-funded scientists led by Dr. Sohrab Shah, senior scientist at the BC Cancer Agency, were published in Nature Genetics (May 2017, Dr. Yi Kan Wang first author). The new subtypes included two from high grade serous cancer (HGSC), the most malignant form, thought to originate in the fallopian tube with early evolutionary acquisition of TP53 mutation and LOH of chromosome 17. These account for up to 70 per cent of all ovarian cancer cases, and 80 per cent of women relapse despite initial treatment success. The other five new subtypes were discovered from three other tumour types: clear cell (CCOC), endometrioid (ENOC), and adult granulosa cell (GCT).

    For the study, tumours from 133 patients with ovarian cancer were subjected to whole-genome sequencing to identify abnormalities in the DNA of ovarian cancer cells. The whole-genome point mutation and structural variation patterns were examined. The study suggests a sub-group of HGSC tumours may have increased capacity to repair events induced by genotoxic chemotherapy. This could explain why these cancers may not be responsive to PARP inhibitors and, in the independent cohorts presented here, show evidence of poor response to the chemotherapy drug cisplatin (typically used to treat ovarian cancer).

    The results show a new stratification of the major histotypes of ovarian cancer using the tumour genome as a biomarker. The genome as a whole reflects aberrant DNA repair processes and thus can be used as means of identifying new therapeutic targets that transcends traditional gene-based biomarkers such as BRCA1 or BRCA2.    

    Further, patterns of changes across the DNA inside cancer cells can help direct drug development efforts for the hardest-to-treat subtypes of ovarian cancer. These findings could be used to develop tests that can direct patients toward new investigational treatments that may help women with subtypes of the disease that are not responsive to standard treatments, as well as illuminate vulnerabilities to exploit in developing future intervention strategies.

    Study: Genomic consequences of aberrant DNA repair mechanisms stratify ovarian cancer histotypes

    Authors: Yi Kan Wang, Ali Bashashati, Michael S. Anglesio, Dawn R. Cochrane, Diljot S. Grewal, Gavin Ha, Andrew McPherson, Hugo M. Horlings, Janine Senz, Leah M. Prentice, Anthony N. Karnezis, Daniel Lai, Mohamed R. Aniba, Allen W. Zhang, Karey Shumansky, Celia Siu, Adrian Wan, Melissa K. McConechy, Hector Li-Chang, Alicia Tone, Diane Provencher, Manon de Ladurantaye, Hubert Fleury, Aikou Okamoto, Satoshi Yanagida, Nozomu Yanaihara, Misato Saito, Andrew J. Mungall, Richard Moore, Marco A. Marra, C. Blake Gilks, Anne-Marie Mes-Masson, Jessica N. McAlpine, Samuel Aparicio, David G. Huntsman & Sohrab P. Shah.

    Funding: We wish to acknowledge generous long-term funding support from the BC Cancer Foundation, supporting the research program of S.P.S. and OvCaRe. The authors graciously thank the Gray Family Ovarian Clear Cell Carcinoma Research Resource, which provided funding critical to this project. Additional funding was provided by a Terry Fox Research Institute New Investigator grant to S.P.S. and a Canadian Cancer Society Research Institute Impact grant to D.G.H. and S.P.S.

    TFRI LINKS, Summer 2017

  • Three 2017 PPG awards announced for cutting-edge projects in leukemia, oncolytic viruses, nanoparticle imaging

    by TFRI Admin | Sep 05, 2017


    (Top left: Dr. Gang Zheng, bottom right: Dr. John Bell, right: Dr. Aly Karsan).

    The Terry Fox Research Institute has invested nearly $21.5-million to renew three 2017 Terry Fox New Frontiers Program Project Grants (PPGs). The projects, based at three leading cancer institutes across Canada, will investigate acute leukemia, oncolytic viruses, and nanoparticle imaging in cancer interventions respectively over the next five years. 

    The successful teams are:

    • The Terry Fox New Frontiers Program Project Grant in [Canadian Oncolytic Virus Consortium: COVCo]; Principal Investigator: Dr. John Bell, Ottawa Hospital Research Institute;

    • The Terry Fox New Frontiers Program Project Grant in Exploiting Pathogenic Mechanisms in Acute Leukemia for Clinical Translation; Principal Investigator: Dr. 
      Aly Karsan, BC Cancer Agency;

    • The Terry Fox New Frontiers Program Project Grant in Porphysome Nanoparticle-Enabled Image-Guided Cancer Interventions; Principal Investigator: Dr. Gang Zheng, Princess Margaret Cancer Centre.

    PPG awards are designed to bring together leading researchers with complementary skills to investigate different aspects of a given area of cancer research. By bringing individual research projects together under one PPG, results can be realized more rapidly and more efficiently. The 2017 Terry Fox New Frontiers Program Project Grants award winners will be profiled in greater detail shortly.

  • Grab your running shoes: Join us on Sept. 17 for the annual Terry Fox Run

    by TFRI Admin | Aug 28, 2017

    This year's annual Terry Fox Run will be held at locations across Canada on Sunday, Sept. 17. Everyone is welcome to participate, regardless of age, athletic ability or socio-economic standing. While the Run does not have an entry fee or minimum donation we do ask all participants to fundraise or make a donation. You can raise funds online, use a pledge sheet or make a donation at the Run site. Whatever your choice, please know that every dollar counts.

    Visit the Terry Fox Foundation website for more information. 


  • Canadian hero Terry Fox’s cancer research legacy lives on: VICE Sports

    by TFRI Admin | Jun 30, 2017


    Two articles published by VICE Sports for Canada 150 are calling Terry Fox the most important athlete in Canadian history whose cancer research legacy lives on.

    “Fox's triumphant Marathon of Hope run was influential in raising much-needed money and awareness for cancer research,” reads the article written by Alex Wong. “His legacy will live on forever, as his impact is still felt across the world today.”

    During the Marathon of Hope, Terry ran 5,000 kilometres across Canada for 143 straight days, all with one leg. Thirty-six years after he passed away from osteosarcoma more than $750-million has been raised in his name for cancer research.

    Founding president and scientific director of The Terry Fox Research Institute Dr. Victor Ling says many doctors and scientists were inspired to enter the profession because of the Marathon of Hope.

    "Because of Terry, and because of who he is, people are willing to work together and collaborate," said Dr. Ling. “We decided we should really do the hard things because that's what Terry would want us to do. He would want us to tackle the biggest challenges."

    To read the full articles and hear more from the Fox family and TFRI-funded researchers, check out:

    Doctors Tell Us How Terry Fox Is Still Influencing Cancer Research

    Terry Fox is the Most Important Athlete in Canadian History

  • Lung cancer screening may save both lives and money, study suggests

    by TFRI Admin | Jun 30, 2017


    New research from a TFRI-funded team suggests screening for lung cancer could save money – and lives – especially if it also identifies other tobacco-related conditions in high-risk individuals.

    This study was published in the Journal of Thoracic Oncology (May 2017), and suggests combining CT screening for multiple conditions with efforts to stop smoking and manage the treatment of non-cancer heart and lung disease could make screening even more cost-effective.

    Lung cancer is the most common cause of cancer death around the world, with 1.6 million deaths and 1.8 million new cases a year. The five-year for survival rate for patients is currently less than 18 per cent, but if caught early enough the disease can be cured for 70 per cent of cases. 

    Lead author Dr. Sonya Cressman (The Canadian Centre for Applied Research in Cancer Control/BC Cancer Agency) says researchers need to think about how to manage lung cancer while focusing on economically viable strategies such as prevention and screening.

    “Screening those at a high-risk gives us the chance to prevent and treat a range of tobacco-related illnesses, and could also offer access to care for individuals who could be otherwise stigmatized or segregated from receiving treatment,” she said.

    Patient data from two major screening trials was examined: The National Lung Cancer Screening Trial (NLST) and the TFRI Pan-Canadian Early Detection of Lung Cancer Study (PanCan). An economic model was built to simulate the costs and benefits of introducing lung cancer screening programs for high-risk people, or those who had a two per cent or higher chance of developing lung cancer within six years.

    Using this data, the team determined the overall cost-effectiveness of the program could be substantially increased if the health of the people being screened were to improve. Focusing on high-risk people could reduce the number of individuals who need to be screened by more than 80 per cent, the study suggests.

    The cost of screening was calculated to be $20,724 per year of life saved, a number considered to be cost-effective compared to the benchmark of $100,000 that is often paid for other cancer interventions in national healthcare.

    “Working with this team of investigators has driven the success of the study,” said Cressman. “The project arose from a strong multidisciplinary collaboration bringing together experts from across Canada who are passionate about public health and willing to invest their protected time in finding ways to optimize the way lung cancer care is delivered.”

    This research was predominantly funded by the Terry Fox Research Institute, the Partnership Against Cancer, and the Canadian Centre for Applied Research in Cancer Control.

    Click here to learn more about TFRI’s Pan-Canadian Early Lung Cancer Detection Study.

    The study's lead author Sonya Cressman. 
  • 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

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