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  • 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

    iStock-621842166

    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

     

  • Whole genome sequencing study helps BC team learn how aggressive follicular lymphoma occurs in patients

    by TFRI Editor | Dec 14, 2016
    Follicular lymphoma (FL), the second most common form of non-Hodgkin lymphoma, is a largely incurable disease of B cells, yet in many cases, because of its indolent nature, survival can extend to well beyond 10 years following diagnosis. Yet in a small number of cases, histological transformation - where fast-growing cells outnumber the smaller, slow-growing cells - or early progression to aggressive lymphoma occurs.

    The events leading to this increased and early mortality are poorly understood. In a study published in PLOS Medicine (Dec. 13, 2016) http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002197, Sohrab Shah and colleagues from the BC Cancer Agency in Vancouver, Canada, investigate the molecular events underlying transformation and progression and show that disparate evolutionary trajectories and mutational profiles drive these two distinct clinical endpoints.

    Using whole genome sequencing, the authors analysed the genome sequence of tumours and matched normal specimens from 41 patients and classified them according to their clinical endpoints: 1) patients who presented with transformation; 2) patients who experienced tumour progression within 2.5 years after starting treatment, without evidence of transformation; and 3) those who had neither transformation nor progression up to 5 years post-diagnosis. In addition, the authors used targeted capture sequencing of known follicular lymphoma associated genes in a larger cohort of 277 patients to investigate discrete genetic events that drive transformation and early progression.

    The authors show that tumours that progress early evolve in different ways than those that transform. Assessing mutations at two time points, and following treatment, they show that for tumours that transform, the cells or clones which constitute the majority of the aggressive tumour were extremely rare at diagnosis, if at all present. In contrast, for early progressive disease the clonal architecture remains similar from the time of diagnosis to relapse, indicating that the diagnostic tumour may already contain the properties that confer resistance to treatment. Analysis of the larger cohort pinpointed key genes and biological processes that were associated with transformation and progression.

    These findings provide a basis for future research on prognostic assay development and potential strategies for monitoring and treatment of patients with FL.

    The study was supported with funding from the Terry Fox New Frontiers Program Project Grant in Forme Fruste Tumours (Grant No. 1023).

    (Press release courtesy of PLOS Medicine)
  • Stem cell-based test predicts leukemia patients' response to therapy to help tailor treatment

    by TFRI Editor | Dec 08, 2016

    TORONTO, Canada – Dec. 7, 2016) – Leukemia researchers at Princess Margaret Cancer Centre, with funding from Terry Fox and others, have developed a 17-gene signature derived from leukemia stem cells that can predict at diagnosis if patients with acute myeloid leukemia (AML) will respond to standard treatment. 

    The findings, published online today in 
    Nature http://www.nature.com/nature/journal/vaop/ncurrent/full/nature20598.htmlcould potentially transform patient care in AML by giving clinicians a risk scoring tool that within a day or two of diagnosis can predict individual response and help guide treatment decisions, says co-principal investigator Dr. Jean Wang, affiliate scientist at the Princess Margaret, University Health Network (UHN). Dr. Wang is also an assistant professor, Faculty of Medicine, University of Toronto and a hematologist at Toronto General Hospital, UHN.

    The new biomarker is named the LSC17 score as it comes from the leukemia stem cells that drive disease and relapse. These dormant stem cells have properties that allow them to resist standard chemotherapy, which is designed to defeat rapidly dividing cancer cells. The persistence of these stem cells is the reason the cancer comes back in patients despite being in remission following treatment. AML is one of the most deadly types of leukemia and the most common type of acute leukemia in adults; it increases in frequency as we age. In Canada, there are more than 1,200 new cases each year. The five-year survival ranges between 20 per cent to 30 per cent and is lower in older people.

    The study authors write that using the LSC17 score to single out high-risk patients predicted to have resistant disease "provides clinicians with a rapid and powerful tool to identify AML patients who are less likely to be cured by standard therapy and who could be enrolled in trials evaluating novel upfront or post-remission strategies."

    The researchers identified the LSC17 score by sampling the leukemia stem cell properties of blood or bone marrow samples from 78 AML patients from the cancer centre combined with molecular profiling technology that measures gene expression. Stanley W. K. Ng, a senior PhD candidate in the lab of Dr. Peter Zandstra at the Institute for Biomaterials and Biomedical Engineering, University of Toronto and co-lead author of the paper, used rigorous statistical approaches to develop and test the new "stemness score", using AML patient data provided by the Princess Margaret leukemia clinic and collaborators in the United States and Europe.

    "We identified the minimal set of genes that were most critical for predicting survival in these other groups of AML patients, regardless of where they were treated. With this core 17-gene score, we have shown we can rapidly measure risk in newly diagnosed AML patients," says Dr. Wang.

    In the study, analysis of patient samples demonstrated that high LSC17 scores meant poor outcomes with current standard treatment, even for patients who had undergone allogeneic stem cell transplantation. A low score indicated a patient would respond well to standard treatment and have a long-term remission.

    The test to measure the LSC17 score has been adapted to a technology platform called NanoString. As the As the research team and international collaborators continue to validate the stemness risk score, plans are under way to test the score in a clinical trial at the Princess Margaret, which now has the NanoString system in its molecular diagnostic laboratory.

    Dr. Wang explains that the fast turnaround time to measure the LSC17 score on the NanoString system will be key to moving the test into the clinic.

    "The LSC17 score is the most powerful predictive and prognostic biomarker currently available for AML, and is the first stem cell-based biomarker developed in this way for any human cancer," says Dr. Wang. "Clinicians will now have a tool that they can use upfront to tailor treatment to risk in AML."

    The research was funded by the Ontario Institute for Cancer Research, the Cancer Stem Cell Consortium via Genome Canada and the Ontario Genomics Institute; the Canadian Institutes of Health Research, Canadian Cancer Society, Terry Fox Foundation; the Canada Research Chair in Stem Cell Biology (Dr. John Dick), the Leukemia & Lymphoma Society of Canada, the Stem Cell Network, the Orsino Chair in Leukemia Research (Dr. Mark Minden), The Princess Margaret Cancer Foundation, and the Ontario Ministry of Health and Long-Term Care. This work was made possible by the generous contributions of blood and bone marrow samples by AML patients to research.   

    View video of Dr. Wang explaining LSC17 score





    ​(TORONTO, Canada – Dec. 7, 2016) – Leukemia researchers at Princess Margaret Cancer Centre have developed a 17-gene signature derived from leukemia stem cells that can predict at diagnosis if patients with acute myeloid leukemia (AML) will respond to standard treatment.

    The findings, published  online today in Nature, could potentially transform patient care in AML by giving clinicians a risk scoring tool that within a day or two of diagnosis can predict individual response and help guide treatment decisions, says co-principal investigator Dr. Jean Wang, Affiliate Scientist at the Princess Margaret, University Health Network (UHN). Dr. Wang is also an Assistant Professor, Faculty of Medicine, University of Toronto and a Hematologist at Toronto General Hospital, UHN.

    The new biomarker is named the LSC17 score as it comes from the leukemia stem cells that drive disease and relapse. These dormant stem cells have properties that allow them to resist standard chemotherapy, which is designed to defeat rapidly dividing cancer cells. The persistence of these stem cells is the reason the cancer comes back in patients despite being in remission following treatment. AML is one of the most deadly types of leukemia and the most common type of acute leukemia in adults; it increases in frequency as we age. In Canada, there are more than 1,200 new cases each year. The five-year survival ranges between 20 per cent to 30 per cent and is lower in older people.

    The study authors write that using the LSC17 score to single out high-risk patients predicted to have resistant disease "provides clinicians with a rapid and powerful tool to identify AML patients who are less likely to be cured by standard therapy and who could be enrolled in trials evaluating novel upfront or post-remission strategies."

    The researchers identified the LSC17 score by sampling the leukemia stem cell properties of blood or bone marrow samples from 78 AML patients from the cancer centre combined with molecular profiling technology that measures gene expression. Stanley W. K. Ng, a senior PhD candidate in the lab of Dr. Peter Zandstra at the Institute for Biomaterials and Biomedical Engineering, University of Toronto and co-lead author of the paper, used rigorous statistical approaches to develop and test the new "stemness score", using AML patient data provided by the Princess Margaret leukemia clinic and collaborators in the United States and Europe.

    "We identified the minimal set of genes that were most critical for predicting survival in these other groups of AML patients, regardless of where they were treated. With this core 17-gene score, we have shown we can rapidly measure risk in newly diagnosed AML patients," says Dr. Wang.

    In the study, analysis of patient samples demonstrated that high LSC17 scores meant poor outcomes with current standard treatment, even for patients who had undergone allogeneic stem cell transplantation. A low score indicated a patient would respond well to standard treatment and have a long-term remission.

    The test to measure the LSC17 score has been adapted to a technology platform called NanoString. As the 

  • Ontario Node Symposium in Toronto draws large crowd; images posted

    by TFRI Editor | Dec 08, 2016
    TFRI's Ontario Node Research Symposium held on Monday, December 5 in Toronto drew over 400 people this year from across the province and beyond to hear a variety of interesting talks on the theme of Innovating Towards Transformative Cancer Care. See images here.

    cover image
    2016 Program and Abstracts Book






    2016 Ontario node program
  • Children from local school pay special visit to TFRI headquarters

    by TFRI Editor | Nov 16, 2016


    School kids visit with Darrell Fox

    TFRI's office in Vancouver, BC welcomed some special guests last month with the visit of three schoolchildren from the Grade 1 class at  St. John's School. The trio, along with a parent and a caregiver, were here to visit with Darrell Fox, Terry's younger brother, who shared with them books and stories about Terry. Pictured above, left to right are: parent Sarah Lee, Andrew McVicar, Darrell Fox, Wesley Russell, caregiver Rowena Renon and Ryan Lee.

  • 2016 Terry Fox Run update: TFRI teams show immense support, with over $105,000 raised through team/t-shirt challenge

    by TFRI Editor | Sep 29, 2016
    TFRI-funded research teams from coast to coast showed their true colours this year, turning out by the dozens in researcher-designated purple T-shirts and forming teams to raise funds for cancer research at the 36th Terry Fox Run on Sunday Sept. 18. 

    Early estimates show the research community's fundraising efforts resulted in over $105,000 raised. The number is based on combining all the known TFRI teams totals that appeared online a few days after the run. In addition, approximately 500 T-shirts were purchased by teams, their friends, families and associates as part of the TFRI Purple T-Shirt Challenge. 

    Notably this year, the Vancouver Prostate Cancer Team raised over $37,000 in donations and purchased 58 purple T-shirts. The team turned out in full force at Stanley Park in Vancouver to run and hear the lead of the long-time program project grant, Dr. Martin Gleave, talk about how Terry Fox funds have had an impact on prostate cancer.(See team photo below).

    Showing another strong performance this year was the Ottawa-based COVCo PPG team led by Dr. John Bell, with approximately $22,000 raised.

    The teams from TFRI's Headquarters(HQ) in Vancouver and the COEUR,CPCBN and CRCHUM in Montreal were neck and neck with $6,300 and $6,625 raised. The HQ team also sold $1,145 in T-shirts in the days before the run and gained more support when members of several BC-based teams joined the HQ effort. 

    New and longstanding teams also showed strong turnouts and support. Drs. Singh, Lupien, Ohashi and Wrana, newly funded award holders, had teams in various locations in Toronto and Oakville run for the cause. TFRI researchers and trainees in Atlantic Canada also had a presence at runs in Halifax and St. John's. On the West coast, Drs. Humphries, Gleave, Lam and Ling headed teams.

    Notable standout individual fundraisers on teams this year were: Dr. Martin Gleave who raised over $20,000 for team VPC; Dr. Peter Black, also with VPC, who raised $11,000+; Dr. Rebecca Auer, with over $8,160 for the COVCo team; and TFRI HQ team member Marlene Manson, who raised over $2,300. 

    TFRI President and Scientific Director Dr. Victor Ling was thrilled by the strong turnout and expressed his thanks to each and every person who helped to make this year's team challenge and fundraising efforts so successful.  

     
    Although the final numbers raised this year through the annual national run are yet unknown, The Terry Fox Foundation said it is quite optimistic that this year will be as strong or better than the totals from last year.  "What we can see is that we are very happy with our online numbers which are on par with last year for donations received and increased in the number of participants who registered online," the Foundation told us. The Foundation expects to know and share more once the results of the school runs, held over the last two weeks, are tallied.  

     Below is a summary list of the TFRI teams that participated in the run and team challenge (according to online records):


    NOTE: IF WE MISSED LISTING YOUR TEAM HERE, PLEASE LET US KNOW!
    IF YOU HAVE A TEAM PICTURE TO SHARE, SEND IT TO US! E-mail info@tfri.ca and we'll be happy to add your name 


    Quebec 
    TFRI Goodman Cancer Research Centre Foxtrotters
    TFRI COEUR, CPCBN, CRCHUM
    TFRI C4 (Canadian Colorectal Cancer Consortium)

    Ontario
    TFRI Hypoxia Team
    TFRI Immunotherapy Network
    TFRI Team Rottapel for Terry
    TFRI-TNBC
    TFRI GBM
    TFRI The MAGICians
    TFRI Team Hippo 
    The Hydra-Killers
    Guelph Cancer Biotherapy Group
    Stemness Program
    COVCo Team

    British Columbia
    Bloodrunners
    TFRI Vancouver Prostate Centre
    TFRI-HQ
    Terry Fox Lung Team

    Atlantic Canada
    BHCRI- Teams in Halifax and St. John's

    TFRI HQ Team

    TFRI HQ team at Stanley Park




    UHN team shirt
     TFRI Hypoxia team customized T-shirt


    VPC team shot
    Vancouver Prostate Centre team

    Wrana team TFR

    Team Hippo (Wrana) PPG team at the Terry Fox Run, UCC/Forest Hill.
    Back row (left to right):  Ted Higgenbotham (Trainee), Emad Heidaryarash (Trainee), Sabrina Sen (Trainee), Liliana Attisano (PI, U of T), Jeff Wrana (Lead PI, LTRI), Frank Sicheri (PI, LTRI), Helen McNeill (PI, LTRI), Shawn Xiong (Trainee), Boris Dyakov (Trainee)

    Front row (left to right): Mandeep Gill (Trainee), Carrie Causing-Henderson (Project Manager), Calley Hirsch (Trainee), Olive and Henry Hirsch, Kai Henderson, Dan Mao (Research Associate)

    Dr. Singh teamTeam GBM (Singh) post-run in Oakville

  • Groundbreaking study finds miR-126 regulates distinct self-renewal outcomes in normal and malignant hematopoietic stem cells

    by TFRI Editor | Sep 29, 2016

    A groundbreaking new publication by Dr. John Dick’s TFRI-funded team has confirmed that miRNA expression patterns are predictive of disease outcome in leukemia, and play a powerful role in governing the fundamental properties that define the “stemness” state of human leukemia stem cells (LSCs).

    Published in Cancer Cell (February 2016), the present study generated a prognostic LSC-associated miRNA signature derived from functionally validated subpopulations of acute myeloid leukemia (AML) samples to investigate miRNA function in human AML stem cells. This was a unique idea in the literature. While over 2,500 validated human miRNA have been identified in our genome, there exists a lack of rigorous studies investigating the role of miRNA in either human hematopoietic stem cell (HSCs) or LSCs.

    Unlike other types of leukemia that have fairly high cure rates, AML’s prognosis is still very grim for certain subtypes. Since LSCs are an important reservoir of disease relapse in AML, understanding LSCs more completely at the molecular level in order to design improved and specific therapies to target these cells is critical for patient outcome.

    The study’s findings suggested that a small non-coding RNA, miR-126, is a highly expressed biomarker of both HSCs and LSCs. Further, despite the miRNA targeting the same proteins in these cells the functional outcome is opposite, whereby increasing the expression of miR-126 in HSCs and LSCs leads to the loss and increase in these cells respectively.

    Leukemia stem cells play central roles in disease progression and recurrence due to their intrinsic capacity for self-renewal and chemotherapy resistance. However, few regulators of human LSCs function are known. The present study established that miRNA played a powerful role in governing the fundamental properties that define the stemness state of human LSCs including quiescence, self-renewal, and chemotherapy response. Further, looking forward it may be possible to therapeutically target the networks that specifically control LSC through perturbation of miR-126 levels.

    Study: miR-126 Regulates Distinct Self-Renewal Outcomes in Normal and Malignant Hematopoietic Stem Cells.

    Authors: Eric R. Lechman, Bernhard Gentner, Stanley W.K. Ng, Jean C.Y. Wang, Luigi Naldini, John E. Dick.

    Funding: This work was supported by grants to L.N. from Telethon (TIGET grant), EU (FP7 GA 222878 PERSIST, ERC Advanced Grant 249845 TARGETING GENE THERAPY), and the Italian Ministry of Health and to J.E.D. from the Canadian Institutes of Health Research, Canadian Cancer Society, Terry Fox Foundation, Genome Canada through the Ontario Genomics Institute, Ontario Institute for Cancer Research with funds from the Province of Ontario, and a Canada Research Chair.

     Reported in TFRI Links, Issue 1, Fall 2016

     

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