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  • Multiple Myeloma Announcement

    by TFRI Editor | Feb 15, 2017
    MULTIPLE-MYELOMA-ANNOUNCEMENT
    TFRI announces its M4 Study today in Saint John
     
    ATTENTION MEDIA:

    • PHOTOGRAPHS AND BIOS (As Available)
    • VIDEOS
      • Principal investigators Drs. Reece and Trudel (PM) explain their role in M4 study Watch

    Dr. Tony Reiman
    Dr. Tony Reiman


    Dr. Reece
    Dr. Reece


    Dr. Suzanne Trudal
    Dr. Suzanne Trudel

    New Brunswick-led national research team aims for tailored treatments for patients with incurable multiple myeloma through Terry Fox Research Institute's $5-million investment

    Wednesday, February 22, 2017

    Saint John, NB - The Terry Fox Research Institute today announced an investment of $5-million for New Brunswick researchers and their colleagues at other cancer centres in Canada to study how new precision medicine tools could improve, and potentially save, the lives of patients diagnosed with multiple myeloma, an incurable cancer of the blood and bone marrow.

    "This $5-million for the Multiple Myeloma Molecular Monitoring Study will enable this world-class research team to apply cutting-edge tools of precision and personalized medicine to better characterize, monitor and treat the disease over time, with the goal of identifying patients whose treatments should be tailored from the current standard of care for the best outcomes possible. We hope this strategy will result in more lives saved. This is our first pan-Canadian study led from New Brunswick and we congratulate Dr. Reiman and his team for bringing together this talented group," said Dr. Victor Ling, TFRI president and scientific director.

    Dr. Tony Reiman, a medical oncologist and professor at the University of New Brunswick, will lead the team, which comprises researchers and clinicians at multiple sites including Vancouver, Calgary, Toronto and Montreal. He hopes the five-year study will result in game-changing new approaches to identifying, treating and monitoring the disease in patients, including those who are at high risk of relapse. He hopes their work will bring strong, evidenced-based results that impact the current standard of care.

    "Currently, patients are all treated and monitored the same way. For patients for whom treatment fails, we need to be able to find new ways of doing things to change that. We're working with sensitive newer techniques to better understand characteristics of the disease that escape our treatments and persist, even during clinical remission, that are going to eventually cause the patient to have a relapse, so we can find better ways to kill those cancer cells that survive the initial treatment," says Dr. Reiman.

    His team in Saint John will organize all the participating centres as well as conduct its own research and receive and bank specimens (blood and marrow) from the 250 myeloma patients that will participate in the project.

    M4 study team members will use tests based on advanced techniques like immunoglobulin gene sequencing, multiparameter flow cytometry, PET scans, circulating tumour DNA analysis, and novel drug resistance assays to evaluate the patient specimens and other biosamples. Principal investigators at the partner sites are: Drs. Donna Reece and Suzanne Trudel, Princess Margaret Cancer Centre; Dr. Nizar Bahlis, University of Calgary; and Dr. François Bénard, BC Cancer Agency.

    The research study is significant to Saint John resident and myeloma patient Susan Collins, who is already an active research participant. "Hope is what sustains all myeloma patients. We hope for a better quality of life and survival until the time when doctors tell their patients myeloma is treatable and curable. Research offers hope for a cure and, in a small way, by supporting studies like this one, I feel I am making a contribution to unlocking the doors to a cure," she remarks. Patients will be recruited by the study investigators at their own sites.

    Multiple myeloma is a deadly disease of the blood and bone marrow. Many people live only months after diagnosis, and only 40 percent are alive after five years. Between 2,000 to 3,000 Canadians are affected by this disease annually. New treatments are need to help save and extend the quality of life for these patients.

    About TFRI
    Launched in October 2007, The Terry Fox Research Institute is the brainchild of The Terry Fox Foundation and today functions as its research arm. TFRI seeks to improve significantly the outcomes of cancer research for the patient through a highly collaborative, team-oriented, milestone-based approach to research that will enable discoveries to translate quickly into practical solutions for cancer patients worldwide. TFRI collaborates with over 70 cancer hospitals and research organizations across Canada. TFRI headquarters are in Vancouver, BC. www.tfri.ca.

    About UNB
    The University of New Brunswick (UNB) is Canada's oldest English-language university. Founded in 1785, the multi-campus institution has a rich history and a dynamic focus on innovation, experiential learning and entrepreneurship. UNB has more than 10,500 students from nearly 100 countries while several thousand more take UNB courses online and at partner institutions around the world.

    For more information, or to schedule an interview, please contact:
    Heather Campbell, Communications Officer, UNB; tel: 506-648-5697, hcampbel@unb.ca,
    Kelly Curwin, Communications, TFRI; tel: 778-237-8158, kcurwin@tfri.ca
     
  • Cambridge MP Bryan May congratulates TFRI and partners in House of Commons

    by TFRI Editor | Feb 15, 2017
    Bryan-May-landscape-2015-12-18
    Bryan May

    In the House of Commons today, Cambridge MP Bryan May congratulated TFRI and its joint pilot project partners -- The Princess Margaret Cancer Centre and the BC Cancer Agency -- for their new partnership to accelerate precision medicine. You can listen to his remarks on You Tube. or read them below.


    Mr Bryan May, (Cambridge, Liberal) : 

    Mr. Speaker, it is my pleasure to bring congratulations and highlight the excellent ongoing work in the fight against cancer.

    The Terry Fox Research Institute, the Princess Margaret Cancer Centre, and the BC Cancer Agency are starting a pilot project to combine the work of investigators and clinicians. This joint project and framework will provide invaluable insight into how to fight cancer.

    This collaboration invests $12 million in four projects: a framework for genomic profiling of cancer patients; optimizing T-cell immunotherapy for ovarian cancer; molecular imaging to improve managing prostate cancer; and building the infrastructure for clinical and genomic data-sharing.

    As we work towards a cure, I want to applaud the leadership and collaboration of the Terry Fox Research Institute, Princess Margaret Cancer Centre, and the BC Cancer Agency. Thanks, and well done.


    Learn more about the pilot project

  • The Terry Fox Research Institute, Princess Margaret Cancer Centre and BC Cancer Agency launch innovative pilot project to accelerate precision medicine in Canada

    by TFRI Editor | Feb 02, 2017


    Pilot project announcement1
    Left to right, unveiling the project name: Dr. Khokha (UHN), Dr. Ling (TFRI), Minister Philpott, Dr. Moore (BC Cancer Agency) and Dr. Wouters (UHN).

    ATTENTION MEDIA:



    Friday, February 3, 2017

    Adam GreenTerry Fox Foundation Terry's Team Member and cancer survivor Adam Green
    Toronto, ON - In a national first, today the Terry Fox Research Institute and two leading cancer centres in Canada -- the Princess Margaret Cancer Centre in Toronto and the BC Cancer Agency in Vancouver -- launched an innovative pilot project to accelerate precision medicine for their cancer patients. The initiative comes at a time when other developed countries are investing heavily in strategies to improve survival from cancer through precision medicine and increased collaboration. The pilot will provide much-needed evidence on how best to roll out a broader vision for data sharing and collaborative translational and clinical research to enable precision medicine for cancer patients.

    The pilot is the first phase for developing and implementing a national program that will link high-performing comprehensive cancer research centres, hospitals and universities and their clinical and laboratory programs across Canada through the Terry Fox Designated Canadian Comprehensive Cancer Centres Network.

    "With the support of the Terry Fox Foundation, TFRI is pleased to have provided catalytic funding to bring this novel and innovative research initiative forward. A project of this scope with two leading cancer care and research institutions working together in this way has never been done before," remarks Dr. Victor Ling, president and scientific director of the Terry Fox Research Institute. "Our ultimate goal through this collaboration is to create a national network of designated Terry Fox comprehensive cancer centres that will be able to deliver excellence in personalized and precision medicine from coast to coast to coast."

    "As a world-leading comprehensive cancer centre, Princess Margaret Cancer Centre has made strategic investments to enable personalized cancer therapy through efforts in immune therapy, genetic sequencing and molecular imaging, thanks to the ongoing support of The Princess Margaret Cancer Foundation. We are excited to participate in this new strategic partnership with the Terry Fox Research Institute and the BC Cancer Agency to enable collaborative efforts in these areas and to accelerate the implementation of effective, targeted therapies for patients," said Dr. Bradly Wouters, executive vice-president, science and research, University Health Network.

    "This project will leverage BC's pioneering contributions in massively parallel sequencing and cutting-edge research in cancer immunology and molecular imaging. Along with our funding partner, the BC Cancer Foundation, we are committed to excellence in cancer care and research and we are pleased to be a founding partner in this initiative. We will share our expertise and learn from each other to make a substantive difference for cancer patients in British Columbia and across Canada" said Dr. François Bénard, vice-president research at the BC Cancer Agency.

    "As a long-time supporter and Terry Fox Run organizer who is inspired by Terry's selfless example, courage and unwavering determination, I am delighted to witness these world-leading organizations working together, bringing hope and innovative care to help more patients survive their cancers," said Pam Damoff, Member of Parliament for Oakville North-Burlington. "Terry Fox reminded us that anything is possible if we try. This partnership is an example of that."

    Through the pilot project, these organizations will provide complementary analyses of specimens (e.g. tumour biopsies and blood samples), identify and determine ways to harmonize their research processes, set up an IT infrastructure for data sharing, and develop resources required to conduct multi-centre precision medicine clinical trials. The initial focus will be on colorectal, ovarian, and prostate cancers, with the goal of improving the health outcomes of patients through treatment by precision medicine.

    Each organization is contributing $4 million over the next two years for a $12-million total investment that will see multidisciplinary teams focus on four specific research thrusts that are institutional priorities: genomics, immunotherapy, molecular imaging and data sharing.

    Networking and shared efforts of comprehensive cancer centres already operate in many other countries, including the US and Europe. A multimillion-dollar continuing annual investment from many funding sources is required for the pan-Canadian network to become fully operational.

    Several national and international cancer experts have voiced their support for the TFRI-led initiative, saying that Canada already has many elements that would contribute to the network's success and its aim to transform cancer care so current and future generations will benefit from precision medicine.

    About The Terry Fox Research Institute (TFRI)

    Launched in October 2007, The Terry Fox Research Institute is the brainchild of The Terry Fox Foundation and today functions as its research arm. TFRI seeks to improve significantly the outcomes of cancer research for the patient through a highly collaborative, team-oriented, milestone-based approach to research that will enable discoveries to translate quickly into practical solutions for cancer patients worldwide. TFRI collaborates with over 70 cancer hospitals and research organizations across Canada. TFRI headquarters are in Vancouver, BC. www.tfri.ca

    About Princess Margaret Cancer Centre, University Health Network
    The Princess Margaret Cancer Centre has achieved an international reputation as a global leader in the fight against cancer and delivering personalized cancer medicine. The Princess Margaret, one of the top five international cancer research centres, is a member of the University Health Network, which also includes Toronto General Hospital, Toronto Western Hospital, Toronto Rehabilitation Institute and the Michener Institute for Education; all affiliated with the University of Toronto. For more information, go to www.theprincessmargaret.ca or www.uhn.ca.

    About BC Cancer Agency
    The BC Cancer Agency, an agency of the Provincial Health Services Authority, is committed to reducing the incidence of cancer, reducing the mortality from cancer and improving the quality of life of those living with cancer. It provides a comprehensive cancer control program for the people of British Columbia by working with community partners to deliver a range of oncology services, including prevention, early detection, diagnosis and treatment, research, education, supportive care, rehabilitation and palliative care. For more information, visit www.bccancer.bc.ca or follow us Twitter @BCCancer_Agency.

    For more information, or to schedule an interview with any of the institutional leads, please contact:

    TFRI: Kelly Curwin, 604-675-8223; 778-237-8158 (cell) kcurwin@tfri.ca
    PM/UHN: Jane Finlayson, Public Affairs, (416)946-2846 jane.finlayson@uhn.ca
    BCCA: Pamela Gole, Communications, 604-877-6282 pamela.gole@bccancer.bc.ca

    Pilot Project Backgrounder (PDF): Click Here

    Q&A about The Terry Fox Canadian Comprehensive Cancer Centres Network (PDF): Click Here
  • Inexpensive algorithm will increase accuracy in subclassification of ovarian cancer, aid in matching treatment to histotype

    by TFRI Editor | Jan 04, 2017

    Martin Koebel


    COEUR image MesMasson
    Top photo: Dr. Martin Koebel, study first author. 
    Above: 
    Endometriod carcinoma (Grade 3) reclassified from high-grade serous carcinoma on the basis of a biomarker-assisted review (the absence of WT1) and the morphology showing a solid neoplasm (upper right) with squamoid features (lower left).

    A biomarker study by COEUR (Canadian Ovarian Experimental Unified Resource), TFRI’s pan-Canadian ovarian cancer research team, examining over 2,000 ovarian cancer tissue samples has led to the development of an inexpensive immunohistochemical algorithm for classifying the five different disease subtypes. Since 2009, the COEUR team has collected the samples from patients across the country with TFRI funding. Biomarkers require large-scale validation, and the COEUR provides an ideal platform.

    Ovarian cancer is the fifth-leading cause of cancer-related deaths in the western world. Over the last decade, it has become clear that it is not a single disease, but consists of five different diseases currently defined by five histotypes, each with unique molecular characteristics, risk factors and clinical behaviour. The five main histotypes of ovarian cancer in descending order of frequency are: high-grade serous carcinoma, clear cell carcinoma, endometrioid carcinoma, mucinous carcinoma, and low-grade serous carcinoma, from which only high-grade serous carcinoma shows high response rates to platinum-based chemotherapy.

    With more than one in four women not responding to standard first-line chemotherapy treatment, having alternate therapies available is critical. By more accurately identifying and assigning ovarian cancers to their proper histotype, there is greater opportunity to personalize treatment and potentially improve outcomes for these patients. Histotype- specific genetic counselling is also emerging, investigating the family risk for certain histotypes (e.g. Lynch syndrome for endometrioid).

    The present study was published in the International Journal of Gynecological Pathology (September 2016) http://journals.lww.com/intjgynpathology/Fulltext/2016/09000/An_Immunohistochemical_Algorithm_for_Ovarian.6.aspx

    Using pooled samples including over 1,000 samples from COEUR, the researchers reclassified histotype using immunohistochemical (IHC) biomarkers. The validity of reclassification was supported by gold standard microscopical review, clinical outcome differences and mutational patterns detected by targeted sequencing in a subset of cases. The highest misclassification occurred in the endometrioid histotype, where most of the changes involved reclassification from endometrioid to high-grade serous carcinoma (the most lethal form).

    Then 1,762 reclassified cases were subjected to several statistical prediction models with a variable IHC marker input. The agreement of the statistical prediction with four IHC markers as input (i.e. WT1, TP53, NAPSA and PGR) was 88% and increased to 93% using an eight marker input. In other words, a limited IHC marker panel can correctly sub-classify approximately 90% of ovarian carcinomas. In conjunction with gold-standard microscopic evaluation, which also has about 90% accuracy, histotype can be assigned with greater than 95% accuracy.

    When treatment options were limited, distinguishing between the different subtypes of ovarian cancer was not as important clinically. Yet, with a growing number of targeted and novel therapies, it is becoming increasingly important to match the patient's cancer with the most appropriate treatment – a goal that starts with a specific and accurate diagnosis. While this immunohistochemical tool can be used for retrospective research cohorts, it can also be applied for clinical trials inclusion, which will likely become histotype-specific disease in their design.

     Study: An immunohistochemical algorithm for ovarian carcinoma typing

     Authors: Martin Köbel, Kurosh Rahimi, Peter F. Rambau, Christopher Naugler, Cécile Le Page, Liliane Meunier, Manon de Ladurantaye, Sandra Lee, Samuel Leung, Ellen L. Goode, Susan J. Ramus, Joseph W. Carlson, Xiaodong Li, Carol A. Ewanowich, Linda E. Kelemen, Barbara Vanderhyden, Diane Provencher, David Huntsman, Cheng-Han Lee, C. Blake Gilks, and Anne-Marie Mes Masson

     Funding: The specimen collection for the COEUR cohort was supported by a grant from the Terry Fox Research Institute. Clinical specimens from the province of Quebec were provided by the Banque de tissus et de données of the Réseau de recherche sur le cancer of the Fonds de recherche du Québec-Santé, which is affiliated to the Canadian Tumor Repository Network. Biologic materials from the province of Ontario were provided by the Ottawa Ovarian Cancer Tissue Bank, the University Health Network Biobank and Ontario Tumour Bank, the later being funded by the Ontario Institute for Cancer Research. Specimens from the province of British Columbia were provided by the BCCA Tumor Tissue Repository and the OvCare Gynecologic Tissue Bank. Finally, specimens from the province of Alberta were provided from the CBCF Tumor Biobank. The AOVT study was supported by the Canadian Institutes of Health Research (MOP-86727).

    Links#2

     

     

  • 2017 New Investigator award recipients announced

    by TFRI Editor | Jan 04, 2017

    Awards to three New Investigators were made byTFRI in late December 2016, for a total investment of $1.3 million.  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.

    TFRI will feature profiles on each recipient on our web site (www.tfri.ca) later this month.

    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.

     

  • Hypoxia team members make game-changing findings about how tumour cells control oxygen consumption

    by TFRI Editor | Jan 03, 2017

    Wouter,B_2011


    Members of TFRI’s hypoxia research team have made some game-changing findings when it comes to understanding how tumour cells regulate their oxygen levels to maximize survival.

    Published in Nature Cell Biology http://www.nature.com/ncb/journal/v18/n7/full/ncb3376.html (July 2016), the study’s authors reported a novel discovery of how tumour cells control the amount of oxygen they consume under conditions of limited oxygen availability.

    Cancer 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.

    It was previously known that the transcription factor hypoxia-inducible factor (HIF) controlled oxygen consumption by mitochondria. This paper demonstrated how oxygen consumption by other processes is inhibited when oxygen is scarce. This information is critical, because cells die if they are unable to shut down this consumption.

    Molecular mechanisms responsible for this regulation were also suggested in the present study. Protein-tyrosine phosphatase-1B (PTP1B) is needed for Her2/Neu-driven breast cancer (BC) in mice, although the underlying mechanism and human relevance is not certain. It was found that PTP1B acts via a protein called RNF213 to suppress α-KGDD activity and non-mitochondrial oxygen consumption – a pathway that is needed for breast cancer to survive in the hypoxic tumour microenvironment.

    This paper (first author Robert S. Banh) opens up an entirely new area of investigation on how cells control oxygen consumption in tumours. Consumption is regulated by the action of a phosphatase that could potentially be targeted with new drugs.

    In addition, the mechanism involves the inactivation of RNF213. The gene encoding this protein is mutated in patients with a rare disease known as Moyamoya. Consequently, the discovery also sheds light on the understanding of this vascular disease, in addition to its groundbreaking relevance to many cancers.

    Study: PTP1B controls non-mitochondrial oxygen consumption by regulating RNF213 to promote tumour survival during hypoxia

    Authors: Robert S. Banh, Caterina Iorio, Richard Marcotte, Yang Xu, Dan Cojocari, Anas Abdel Rahman, Judy Pawling, Wei Zhang, Ankit Sinha, Christopher M. Rose, Marta Isasa, Shuang Zhang, Ronald Wu, Carl Virtanen, Toshiaki Hitomi, Toshiyuki Habu, Sachdev S. Sidhu, Akio Koizumi, Sarah E.Wilkins, Thomas Kislinger, Steven P. Gygi, Christopher J. Schofield, James W. Dennis, Bradly G. Wouters, and Benjamin G. Neel

    Funding: This work was funded by NIH grant R37 CA49152 and Canadian Institutes of Health Research (CIHR) grant 120593 (to B.G.N.), CIHR grant 62975 (to J.W.D.), CIHR grant 136956 (to S.S.S.), CIHR grant 133615 (to T.K.), Terry Fox New Frontiers Research Program PPG09-02005 (to B.G.W.), Cancer Research-UK and the Wellcome Trust (to S.E.W. and C.J.S), NIH grant GM96745 (to S.P.G.) and Kiban Kenkyu grant A-25253047 to A.K. Work in the Neel and Wouters laboratories was partially supported by the Princess Margaret Cancer Foundation and the Ontario Ministry of Health and Long Term Care.

     

     

  • TFRI-funded team identifies two new inhibitors that show potential in combination therapies for adult brain cancer

    by TFRI Editor | Jan 03, 2017

      glioblastoma-supplied

    A study by TFRI researchers investigating potential new drugs to treat glioblastoma (GBM) patients has identified an epigenetic-modifier drug which, taken in combination with standard chemotherapy, extends life in mouse models. Further, a second inhibitor that limits tumour growth and shows no toxicity to cells may also hold promise as a treatment therapy.

    Evidence generated in this study, published in Oncotarget http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=10661 (July 2016), strongly suggests that drugs targeting epigenetic modifiers should be considered as candidate therapeutics for GBM. 

    Glioblastoma multiforme (GBM) is the most lethal and aggressive adult brain tumour with a life expectancy from diagnosis of only 15 months – and there are currently no effective treatments

    Since epigenetic alterations are hallmarks of many tumours, including GBM, epigenetic modifiers have emerged as attractive targets for therapeutic intervention. Recently, Cheryl Arrowsmith (Princess Margaret, Toronto) and the Structural Genomics Consortium created a library of drugs that target various epigenetic modifiers and, for the first time for GBM, this library was used to identify candidate drugs that target multiple primary and highly tumourigenic GBM cell lines from patients.

    One of the main issues with current drugs that inhibit epigenetic modifiers is that few can cross the blood-brain barrier and enter the central nervous system. The present study identified one that efficiently enters the brain, a class I HDAC inhibitor which, when taken in combination with the standard chemotherapy drug Temozolomide (TMZ), extended survival in mice models.

    Further, the novel EZH2 inhibitor UNC1999 exhibited low micromolar cytotoxicity in vitro on a diverse collection of brain-tumour intiating cell lines (BTICs), synergized with the steroid medication dexamethasone (DEX). It was also found to suppress tumour growth in vivo in combination with DEX.

    TFRI’s pan-Canadian GBM team comprises a cross-Canada collaboration of cellular and molecular biologists, geneticists, pathologists, chemists, pharmacologists, preclinical researchers, and drug discovery experts. 

    Study: Small molecule epigenetic screen identifies novel EZH2 and HDAC inhibitors that target glioblastoma brain tumor-initiating cells

    Authors: Natalie Grinshtein, Constanza C. Rioseco, Richard Marcellus, David Uehling, Ahmed Aman, Xueqing Lun, Osamu Muto, Lauren Podmore, Jake Lever, Yaoqing Shen, Michael D. Blough, Greg J. Cairncross, Stephen M. Robbins, Steven J. Jones, Marco A. Marra, Rima Al-awar, Donna L. Senger, David R. Kaplan.

    Funding: This work was supported by grants from the Terry Fox Research Institute and the Canadian Stem Cell Network.

    Links#2

     

     

  • How differences in the germline influence the type of prostate cancer that arises

    by TFRI Editor | Jan 03, 2017
    candidate list RNA

    Top 20 IncRNAs associated with risk for prostate cancer. (Image supplied)

    When it comes to treating prostate cancer, the news is predominantly positive: a combination of early detection and treatment by radiotherapy and surgery mean that most patients will not die of the disease. Still, its incidence continues to rise and prostate cancer remains the most frequently diagnosed non-skin malignancy in Canadian men.

     A large number of patients are likely being over-treated today, a dilemma that a Nature Genetics study http://www.nature.com/ng/journal/v48/n10/full/ng.3637.html (August 2016) involving TFRI-funded researchers aimed to resolve by understanding how differences in the germline influence the type of prostate cancer that arises. The study results provide key insight into how a patient’s normal, healthy genome can change the way prostate cancer will develop, and suggests that existing diagnostics assays can be improved considering that information.

     Led by TFRI New Investigator Dr. Housheng Hansen He (UHN), the international team identified 45 candidate lncRNAs associated with risk for prostate cancer by using integrative analysis of the lncRNA transcriptome with genomic data and single nucleotide polymorphisms (SNPs) data from prostate cancer genome-wide association studies (GWAS).

    The mechanism underlying the top lncRNA hit, PCAT1, was then evaluated, and it was found that PCAT1 promotes prostate cancer cell proliferation and tumour growth in vitro and in vivo. A germline SNP that increases the risk of contracting cancer was identified, and demonstrated that it does so by changing the regulation of the relatively poorly understood gene. The study also identified a previously unknown function of PCAT1 in the androgen signaling pathway and that PCAT1 may promote prostate tumorigenesis through multiple pathways.

    These findings suggest that modulating lncRNA expression is an important mechanism for risk-associated SNPs in promoting prostate transformation. In the future, patients who have lncRNAs, such as high-risk PCAT1, can be treated more robustly, while those who are classified as lower risk based on their genome can avoid the risks and consequences of overtreatment. 

    These results were validated in primary patient tumours studied in the Canadian Prostate Cancer Genome Network, a national project studying the genomics of prostate cancer. Given the success of the present study, the team suggests similar work should be performed to characterize risk-associated lncRNAs in all cancer types.

    Study: Modulation of long noncoding RNAs by risk SNPs underlying genetic predispositions to prostate cancer

    Authors: Haiyang Guo, Musaddeque Ahmed, Fan Zhang, Cindy Q Yao, SiDe Li, Yi Liang, Junjie Hua, Fraser Soares, Yifei Sun , Jens Langstein , Yuchen Li , Christine Poon , Swneke D Bailey , Kinjal Desai, Teng Fei, Qiyuan Li, Dorota H Sendorek , Michael Fraser , John R Prensner, Trevor J Pugh , Mark Pomerantz, Robert G Bristow, Mathieu Lupien , Felix Y Feng , Paul C Boutros, Matthew L Freedman, Martin J Walsh & Housheng Hansen He.

    Funding: P.C.B. is supported by a Terry Fox Research Institute New Investigator Award and a CIHR New Investigator Award.

    Links#2

     

     

     

  • Personalizing treatment for patients with the most common malignant childhood brain tumour

    by TFRI Editor | Jan 03, 2017
    medulloblastoma-image-Mabbott
    Colour 3-D computed tomography brain scan showing a medulloblastoma tumour (red). Image processing techniques have been used to cut away part of the skull. The blue structures are the fluid-filled ventricles in the centre of the brain. 

     

    A TFRI-funded research team studying the most common type of brain tumour in children recently demonstrated the benefits of personalizing treatment for children with medulloblastoma.

    With a mortality rate of 30 to 40 per cent among children who are diagnosed with the disease, those who do survive often experience negative side effects from surgery, radiation, and chemotherapy.

    The research, led by the lab of Dr. Donald Mabbott and his graduate student Iska Moxon-Emre at Toronto’s SickKids Hospital, was published in the Journal of Clinical Oncology http://ascopubs.org/doi/full/10.1200/JCO.2016.66.9077 (August 2016). The paper suggests that children with less aggressive subtypes of medulloblastoma had spared intelligence -- and their survival was not compromised -- when they received less radiation.

    For the study, data from 121 children who were treated between 1991 and 2013 at the Hospital for Sick Children (Toronto,Ontario), Children’s National Health System (Washington, DC), or the Lucile Packard Children’s Hospital (Palo Alto, CA) was compared.

    They found that children in two of four subgroups -- WNT and Group 4 -- benefitted from less aggressive treatment, and there was no increase in mortality. Further, the evidence suggests that subgrouping patients based on their genetics can help identify those with lower-risk disease who may be candidates for less aggressive therapy to spare their cognitive function, keeping both survival rates and functionality high.

    Interestingly, patients with the sonic hedgehog (SHH) subtype had the lowest incidence of mutism and motor deficits, common post-surgical complications. This finding indicates that the subgroups differ in their functional outcomes, and further highlights the value of using subgroup information to help guide treatment for patients with medulloblastoma.

    This was the first study of its kind to report on intellectual outcome in molecular subgroups of medulloblastoma, and the results promise to benefit future patients.

    StudyIntellectual outcome in molecular subgroups of medulloblastoma

    AuthorsIska Moxon-Emre, Michael D. Taylor, Eric Bouffet, Kristina Hardy, Cynthia J. Campen, David Malkin, Cynthia Hawkins, Normand Laperriere, Vijay Ramaswamy, Ute Bartels, Nadia Scantlebury, Laura Janzen, Nicole Law, Karin S. Walsh, and Donald J. Mabbott 

    FundingSupported by Canadian Institutes of Health Research, Brain Canada, Pediatric Oncology Group of Ontario, and the MAGIC (Medulloblastoma Advanced Genomics International Consortium) project. The MAGIC project acknowledges funding from Genome Canada, Genome British Columbia, Terry Fox Research Institute, Ontario Institute for Cancer Research, Pediatric Oncology Group Ontario, the family of Kathleen Lorette, Clark H. Smith Brain Tumour Centre, Montreal Children’s Hospital Foundation, Hospital for Sick Children, Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, and B.R.A.I.N. Child (Brain Tumour Research Assistance and Information Network).

    Links#2

     

     

     
     

  • Clusterin knockdown sensitizes prostate cancer cells to therapies by modulating mitosis

    by TFRI Editor | Jan 03, 2017

    clusterin cropped

    A study by a TFRI-funded team based at the Vancouver Prostate Centre has found that silencing a key driver of castrate-resistant prostate cancer and regulating cell division (mitosis) can improve patient drug response.

    The present study, led by Dr. Martin Gleave and published in EMBO Molecular Medicine http://onlinelibrary.wiley.com/doi/10.15252/emmm.201506059/full  (May 2016), explored the biological effects of clusterin (CLU) on mitosis, finding that silencing CLU-induced activation of Cdc25C makes cancer cells more sensitive to mitotic-targeting agents such as chemotherapy.

    Therefore, drugs that can be used to inhibit CLU could improve patient’s treatment response when used in combination with standard treatments. CLU is a stress-activated molecular chaperone that can activate treatment resistance to taxanes (drugs that block cell division).

    Further, the present study authored by Nader Al Nakouzi demonstrated for the first time that resistance to taxanes may occur via Cdc25C-Wee1-MPF regulation, and that co-targeting Wee1 induction caused by inhibiting CLU could be a new and effective method for overcoming drug resistance in prostate cancer patients and may also increase survival rates.

    Prostate cancer is the third leading cause of cancer-related death in Canadian men, and one of the most common cancers for this demographic. It initially responds well to hormone therapy, but can often become resistant to treatment, an outcome that is linked to poor prognosis.

    This study data complements prior work by Dr. Gleave’s team in developing anti-clusterin drugs to overcome treatment resistance and increase survival for patients. It also builds on other project work related to other drugs currently in clinical trials, and therapies that inhibit Hsp27 and ERG, which encode proteins typically mutated in cancer.

    Study: Clusterin knockdown sensitizes prostate cancer cells to taxane by modulating mitosis

    Authors: Nader Al Nakouzi, Chris Kedong Wang, Eliana Beraldi, Wolfgang Jager, Susan Ettinger, Ladan Fazli, Lucia Nappi, Jennifer Bishop, Fan Zhang, Anne Chauchereau, Yohann Loriot & Martin Gleave

    Funding: This project was supported by a Terry Fox New Frontiers Program Project Grant TFF116129, a Prostate Cancer Foundation of British Columbia (PCFBC) Grant 2013, and a Prostate Cancer Canada Team Grant T2013-01. We would like to thank Mr. Dulguun Battsogt for his technical support and Mr. Robert Bell for his help with the statistical analysis.

     Links #2

     

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