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  • 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

     

     

  • 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

    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.

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