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  • 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

     

  • Montreal team discovers new molecular pathway key to understanding fat/cancer links

    by TFRI Editor | Sep 29, 2016

    fat tissue

    A new publication from the TFRI-funded team at McGill University (Goodman Cancer Centre) studying oncometabolism and molecular pathways
    is bringing new hope to the battle against obesity, cardiovascular disease and diabetes with the significant discovery of a new molecular pathway that has the ability to turn fat storage cells into fat burning cells.

    Published in Genes and Development (April 2016), the paper details how knocking out the tumour suppressor protein folliculin (FLCN) (which also helps regulate fat cells) in mice triggers a series of biomolecular signals that switch the cells from storing adipocytes to burning them.

    Obesity is a major health challenge around the globe, and is a major risk factor for metabolic disorders such as Type 2 diabetes, cardiovascular diseases and certain cancers. Scientists have long accepted the concept of white and brown fat cells: where white fat is deemed unhealthy and works as energy storage tissue while brown fat mainly burns energy to produce heat and keep body temperature constant. Beige fat has also been recently discovered, and functions somewhere in between white and brown fat. Conversion from white fat cells to beige or brown fat cells is a very desirable effect in obesity,and diabetic and metabolic syndrome indications, since excess energy in the body is not stored in fat tissue; it is burned in brown or beige fat tissue.

    The present study demonstrated that Flcn deletion in adipose tissue results in activation of an AMPK/PGC-1α/ERRα molecular axis, promoting mitochondrial biogenesis, oxygen consumption, FAO, UCP expression and heat production, thereby shifting white adipocytes from “lipid storage compartments” to active sites of lipid metabolism.

    Further, deletion of Flcn in mouse adipose tissues leads to a complete metabolic reprogramming of both white and brown adipocytes, leading the mice to exhibit significantly higher energy expenditure associated with an increase in mitochondrial respiration.

    In a nutshell, mice without Flcn stayed slim and burned more fat as energy as the fat storage units turned into fat burning engines through the stimulation of beige and brown fat pathways. The discovery of the folliculin pathway lays the groundwork for new medications to be developed that will stimulate the ‘browning’ process, potentially reducing the risk of obesity, cardiovascular disease, and diabetes.

    Study: Chronic AMPK activation via loss of FLCN induces functional beige adipose tissue through PGC-1α/ERRα

    Authors: Ming Yan, Étienne Audet-Walsh, Sanaz Manteghi,Catherine Rosa Dufour, Benjamin Walker, Masaya Baba, Julie St-Pierre, Vincent Giguère, and Arnim Pause.

    Funding: This work was funded by the Kidney Foundation of Canada KFOC100021 (A.P.), the Myrovlytis Trust (A.P.), a Terry Fox Research Institute Program Project Team Grant on Oncometabolism (116128), the New Innovation Fund CFI 21875, CIHRMOP-125885 (V.G.), and McGill University. This work was funded by the Kidney Foundation of Canada KFOC100021 (A.P.), the Myrovlytis Trust (A.P.), a Terry Fox Research Institute Program Project Team Grant on Oncometabolism (116128), the New Innovation Fund CFI 21875, CIHR MOP-125885 (V.G.), and McGill University.

     TFRI Links, Fall 2016



  • Dual expression study helps identify B-cell lymphoma patients at high risk for CNS relapse

    by TFRI Editor | Sep 29, 2016

    non-Hodgkin's lymphoma cells

    Despite improvements in outcome in diffuse large B-cell lymphoma (DLBCL) in the monoclonal antibody rituximab treatment era, central nervous system (CNS) relapse continues to occur and typically is incurable. Identifying high-risk patients is essential to focus on effective prophylaxis strategies.  To date, there have not been any identified robust biomarkers to predict those at high risk.  Previous seminal studies from the BC Cancer Agency have identified MYC and BCL2 dual expression to be associated with poor outcome.  Importantly, a study published in Blood (May 2016) by a TFRI-funded team suggests that dual expression of MYC and BCL2 tested by immunohistochemistry (IHC) is associated with an increased risk of CNS relapse.  

    DLBCL is the most common type of non-Hodgkin lymphoma (NHL), comprising around 30 to 40 % of all cases. Initial chemotherapy treatments are often successful in more than half of patients, but many patients still relapse. Dual translocation of MYC and BCL2, also known as “double-hit lymphoma,” has been associated with a high risk of central nervous system (CNS) relapse, yet the impact of dual expression of MYC and BCL2 (dual expressers) on the risk of CNS relapse remains unknown.

    In the present study, 428 patient biopsies from newly diagnosed DLBCL treated with curative-intent rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were collated from existing tissue microarrays and were evaluated for MYC and BCL2 dual protein expression by IHC. The cumulative risk of CNS relapse was higher in dual expressors and defined a high-risk group with the non-GCB/ABC DLBCL subtype (~16% vs ~3%, P=.01).  Further, MYCBL2 dual expression remained a significant variable in multivariate analyses, in addition to the recently described CNS risk model (CNS-IPI (international prognostic index) where those patients with a high CNS-IPI risk score and dual expression of MYC and BCL2 had a CNS relapse risk of ~23%. 

    These results have immediate and direct clinical implications, as patients in this category can be screened with CNS-directed staging studies and strongly considered for CNS prophylaxis strategies.  Further studies are ongoing to define additional biomarkers and genetic factors that can help refine the identification of a high-risk CNS relapse group to focus aggressive CNS-directed staging procedures and select patients for prophylactic strategies.

    Study: Impact of dual expression of MYC and BCL2 by immunohistochemistry on the risk of CNS relapse in DLBCL

    Authors: Kerry J. Savage, Graham W. Slack, Anja Mottok, Laurie H. Sehn, Diego Villa, Roopesh Kansara, Robert Kridel, Christian Steidl, Daisuke Ennishi, King L. Tan, Susana Ben-Neriah, Nathalie A. Johnson, Joseph M. Connors, Pedro Farinha, David W. Scott, and Randy D. Gascoyne.

    Funding: This work was supported by a Program Project Grant No. 1023 from the Terry Fox Research Institute, and by grants from the Canadian Institutes of Health Research and the British Columbia Cancer Foundation.

    TFRI Links, Fall 2016


     


     


  • Ovarian cancer: Mapping the clonal spread

    by TFRI Editor | Sep 29, 2016

    Dr. Shah
    Dr. Sohrab Shah

    A team of B.C.-based, TFRI-funded scientists are breaking new ground with a recent study that tracked the clonal spread and 
    intraperitoneal mixing of high-grade serous ovarian cancer (HGSOvCa), the deadliest subtype of the disease.

    Their findings, published in Nature Genetics (July 2016), mapped the different patterns of metastatic spread in the peritoneal cavity of women with HGSOvCa. At least two divergent modes of intraperitoneal metastasis were identified, highlighting the interplay between genomically diverse clones and their migratory potential prior to treatments in this subtype of ovarian cancer.

     As many as 80% of  (HGSOvCa) patients suffer relapse after initial response to treatment. It is characterized by widespread and early intraperitoneal spread to organs, and the patients account for nearly 70% of all ovarian cancer cases.

    The present study provided valuable information about the composition of the cancer cell groups in metastatic cancers. It was found that many different types of cancer cells make up a patient’s tumour, which may explain why some cells are eradicated by treatment while others become resistant, eventually resulting in the patient's relapse. HGSOvCa also appears to have the unique ability to metastasize prolifically throughout the abdomen, which often results in patient death.

    These findings suggest that some cancer cells may have had pre-existing properties of resistance before a patient begins treatment. Understanding this could lead to women being given a more aggressive, multi-treatment approach at the beginning of their therapy in an effort to prevent patient relapse, versus waiting until the cancer has already returned. Future research will help to define cell migration maps in more patients, with a focus on ascertaining which cells are resistant to treatment, and enabling researchers to create predictive tools to better inform future care for women with this lethal type of ovarian cancer.

    Study: Divergent modes of clonal spread and intraperitoneal mixing in high-grade serous ovarian cancer

     Authors: Andrew McPherson, Andrew Roth, Emma Laks, Tehmina Masud, Ali Bashashati, Allen W Zhang, Gavin Ha, Justina Biele, Damian Yap, Adrian Wan, Leah M Prentice, Jaswinder Khattra, Maia A Smith, Cydney B Nielsen, Sarah C Mullaly, Steve Kalloger, Anthony Karnezis, Karey Shumansky1, Celia Siu, Jamie Rosner, Hector Li Chan, Julie Ho, Nataliya Melnyk, Janine Senz8, Winnie Yang, Richard Moore, Andrew J Mungall, Marco A Marra, Alexandre Bouchard-Côté, C Blake Gilks, David G Huntsman, Jessica N McAlpine, Samuel Aparicio & Sohrab P Shah.

    Funding: This work was funded by the BC Cancer Foundation. In addition, the groups of S.P.S. and S.A. receive operating funds from the Canadian Breast Cancer Foundation, the Canadian Cancer Society Research Institute (grant 701584), the Terry Fox Research Institute (TFRI), Genome Canada/ Genome BC (173-CIC and 177-EVO), the Canadian Institutes of  Health Research (CIHR) (MOP-115170, MOP-126119, and FDN-143246), a new investigator grant to J.N.M. (MSH-261515), and a TFRI new investigator award to S.P.S. S.P.S. and S.A. are supported by Canada Research Chairs.

    TFRI LInks, Fall 2016

  • New class of small molecules enhances OV replication

    by TFRI Editor | Sep 29, 2016

    An innovative paper by Dr. Jean-Simon Diallo  (TFRI-funded Canadian Oncolytic Virus Consortium (COVCo) and collaborators Drs. Jeffrey Smith and Christopher Boddy was published in Scientific Reports (May 2016).  They discovered and developed a class of new small molecule compounds that selectively enhance oncolytic viruses (OV) in cancer tissue, making them more likely to destroy tumour cells and eradicate the disease.

    The use of engineered viral strains such as gene therapy vectors and oncolytic viruses to selectively destroy cancer cells is poised to make a major impact in the clinic and to revolutionize cancer therapies. Yet in clinical studies, OV therapy has shown highly variable rates of patient response. The heterogeneous nature of tumours is widely accepted to be a major obstacle for OV therapeutics and highlights a need for strategies to improve the efficacy of viral replication.

    The present study looked at the development of a new class of small molecules for selectively enhancing OV replication in cancer tissue. Medicinal chemistry studies led to the identification of compounds that enhance multiple OVs and gene therapy vectors. The lead compounds increase OV growth by up to 2,000-fold in vitro and demonstrate remarkable selectivity for cancer cells over normal tissue ex vivo and in vivo.  These small molecules also demonstrate enhanced stability with reduced electrophilicity and are well-tolerated in animals. This pharmacoviral approach expands the scope of OVs to include resistant tumours, further potentiating this transformative therapy.

    The process of selecting promising molecule compounds may be like looking for a needle in a haystack, but the present study’s results were very promising. Nearly 30,000 molecules were screened initially to find just over a dozen highly active ones.  From there, the team selected a lead candidate that they used as a model to create nearly 100 more molecules closely related to that initial lead compound, from which a handful of compounds that hold promise for human applications were identified --  including one they are very excited about based on promising animal studies. 

    In summary, the current study has developed new molecular tools in the search for a cure for cancer, as well as identified credible drug candidates for evaluation in OV clinical trials. In addition, these new molecular tools provide an opportunity to better understand how cells protect themselves from viral infection. The applications of this span beyond cancer but are also relevant for treating hereditary diseases using gene therapy, and also to the development and manufacturing of vaccines.

    small molecules

    Study: First-in-class small molecule potentiators of cancer virotherapy.

    Authors: Mark H. Dornan, Ramya Krishnan, Andrew M. Macklin, Mohammed Selman,Nader El Sayes, Hwan Hee Son, Colin Davis, Andrew Chen, Kerkeslin Keillor, Penny J. Le, Christina Moi, Paula Ou, Christophe Pardin, Carlos R. Canez, Fabrice Le Boeuf, John C. Bell, Jeffrey C.  Smith, Jean-Simon Diallo & Christopher N. Boddy.

    Funding: JSD and JCB receive funding from the Terry Fox Research Institute program project grant (grant # TFF 122868) and a The Lotte & John Hecht Memorial Foundation Innovation Grant of the Canadian Cancer Society (grant #2012-701460).  CNB, JSD and JCS are supported from the Canadian Institutes of Health Research (CIHR) and the National Science and Engineering Research Council (NSERC) through a Collaborative Research Project Grant.  Additional NSERC funding supports CB, JCS and MHD.


    TFRI Links, Fall 2016

  • Ultrasound, imaging effective tools to monitor treatment response

    by TFRI Editor | Sep 29, 2016

    Terry Fox-funded researchers have made a critical finding in monitoring breast cancer patient response to chemotherapy treatment: patient response to treatment can be detected in as little as one week by using optics and ultrasound respectively instead of waiting the traditional four to six months. Their findings were published in Oncotarget (March 2016).

    Breast cancer is the second-leading cancer related death in women, and there are more than 17 different tumour subtypes. About 10 to 15 % of tumours fall under the category of locally advanced breast cancer (LABC), defined as Stage 3 to 4  tumours that are greater than five centimetres in size, and potentially involving one or more lymph nodes. Further, survival outcomes for LABC are poor: Only 25% of women may achieve complete pathological response and up to 46% of patients may develop recurrence within five years.

    The present study evaluated pathological response to neoadjuvant chemotherapy using quantitative ultrasound (QUS) and diffuse optical spectroscopy imaging (DOSI) biomarkers of LABC in 22 different patients at weeks 0, 1, 4, 8, and post-operatively. Cell death detection was done using quantitative ultrasound and spectroscopic methods the team developed, while the optical work tracked changes in hemoglobin and blood flow.

    The results were promising: QUS and DOSI demonstrated potential as coincident markers for treatment response and may potentially facilitate response-guided therapies. Multivariate QUS and DOSI parameters were shown to increase the sensitivity and specificity of classifying LABC patients as early as one week after the start of treatment.

    The present publication is the first in-human study showing that QUS and DOSI work effectively both alone and together, and could be used as low-cost tools to personalize a patient’s chemotherapy treatment. The potential impact in the clinic is huge: a patient would no longer be required to undergo four to six months of treatment that isn’t going to work. Instead, treatment success can be very quickly assessed and changed to a different type of chemotherapy if necessary.

    Study: Multiparametric monitoring of chemotherapy treatment response in locally advanced breast cancer using quantitative ultrasound and diffuse optical spectroscopy.

    Authors: William T. Tran, Charmaine Childs, Lee Chin, Elzbieta Slodkowska, Lakshmanan Sannachi, Hadi Tadayyon, Elyse Watkins, Sharon Lemon Wong, Belinda Curpen, Ahmed El Kaffas, Azza Al-Mahrouki, Ali Sadeghi-Naini, Gregory J. Czarnota

    FundingThis work was supported by the Terry Fox Foundation and the Canadian Breast Cancer Foundation.

    Reported in TFRI Links, Issue 1, Fall 2016

     

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