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  • 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

     

  • TFRI's 2017 ASM meeting date, location

    by TFRI Editor | Sep 27, 2016

    In 2017,TFRI will hold its Annual Scientific Meeting on Saturday, November 4th to coincide with the national meeting of the Canadian Cancer Research Conference in Vancouver (Nov. 5-7th). Stay tuned for more details.

    Photo below: TFRI researchers and trainees gathered in Vancouver in May 2016 for our 7th Annual Scientific Meeting.

    2016 ASM group shot

  • TFRI ANNOUNCES 2016 FUNDING COMPETITION AWARD RECIPIENTS

    by TFRI Editor | Sep 07, 2016

     Six stellar TFRI research teams will use $27.3 million to engineer precision medicine across a range of cancers

    FOR RELEASE 1PM EST

    Wednesday, Sept 7, 2016

     

    Attention Editors:

    > The Terry Fox Run is being held on Sunday, Sept. 18th
    The brain cancer project will focus on new treatments for glioblastoma (The Tragically Hip’s Gord Downie announced in May he has this cancer)

    Vancouver, BC – Six outstanding Canadian research teams will use $27.3 million in new funding to engineer precision medicines for patients whose cancer has relapsed or for whom current treatments are ineffective or non-existent.

    The Terry Fox Research Institute teams are conducting research into brain, colorectal, prostate, breast and ovarian cancers and lymphoma at research centres and hospitals across the country. Some studies will include undertaking trials for immunotherapy -- using the body’s immune system to kill cancer cells.

    The majority of the funding ($26.1 million) is being provided by The Terry Fox Foundation through funds raised annually from the Terry Fox Run. National funding partner, The Canadian Institutes of Health Research, is contributing $1.2 million to co-invest in the project with the goal of finding more effective treatment for a hard-to-treat breast cancer called triple negative breast cancer.

    “We thank the Terry Fox Foundation and the Canadian Institutes of Health Research for making these investments possible.  Our shared goal is to provide cancer patients with the right remedy for the right cancer at the right time – so precision medicine will help us to find more cures for cancer.  The projects being funded today are judged by international experts as being excellent, leading-edge and having the best potential for us to achieve this goal,” says Dr. Victor Ling, TFRI president and scientific director.

    “We are delighted to see our supporter funds invested across such a range of cancers since Terry Fox believed in funding all types of cancer research. We hope Canadians will continue to show their support for Terry’s cause and cancer research on Sunday, September 18 by participating in and donating to a Terry Fox Run in their community,” said Terry Fox Foundation executive director Britt Andersen. The Terry Fox Run will be held on Sunday, September 18.

    The Terry Fox New Frontiers Program Project Grants (PPGs) and Translational Research Programs are highly competitive. Following international peer review, funds are awarded annually to teams of investigators to support breakthrough and transformative biomedical research which may form the basis for innovative cancer prevention, diagnosis and/or treatment. See below the investment breakdown by project and province:

    PAN CANADIAN (Ontario, Quebec, British Columbia and Alberta)

    Dr. Pamela Ohashi, director, immune therapy program, Princess Margaret Cancer Centre, University Health Network (UHN), and colleagues will develop immunotherapies and undertake clinical trials through The Immunotherapy Network to improve survival for women diagnosed with high-grade serous ovarian cancer, the deadliest of the ovarian cancers. (Award: $5.41M over 5 years)

    ONTARIO

    Awards of  $2.25 M each over 3 years:

    Dr. Mathieu Lupiensenior scientist and oncologist and colleagues at UHN (Toronto), will focus on effective therapies, including immunotherapy, to improve treatments available to women with triple negative breast cancer. The Canadian Institutes of Health Research is funding 50 per cent of this award.

     Dr. Sheila Singhpediatric neurosurgeon at McMaster University (Hamilton), and colleagues at the University of Toronto, will study glioblastoma multiforme (brain cancer) in its recurrent and relapsed form, rather than the original tumour (s), to  develop new and effective treatments to improve survival

    Dr. Jeff Wrana
    senior investigator at the Lunenfeld-Tanenbaum Research Institute, Sinai Health System and co-investigators there and at the U of T (Toronto), will study how an important body mechanism, the Hippo Pathway, is inactivated, thus enabling abnormal tissue growth, and ways to reactivate it. Their work will focus on colorectal cancer using unique “mini-gut” models

    BRITISH COLUMBIA

    Awards of $7.5 M each over 5 years:

    Dr. Joseph Connors, clinical director at the Centre for Lymphoid Cancer, BC Cancer Agency (Vancouver), and colleagues (University of British Columbia, BC Cancer Agency, and Simon Fraser University ) will continue novel and innovative research in lymphoma and related cancers to provide new tests and treatments that will benefit those patients

    Dr. Martin Gleave
    executive director, Vancouver Prostate Centre (VPC), and team members (VPC, UBC, and SFU), to continue world-class research to provide new treatments for men whose prostate cancer has become resistant to current therapies.

     Quotes from Funding Partners

    “CIHR is pleased to partner with the Terry Fox Research Institute and theTerry Fox Foundation and support Dr. Mathieu Lupien and his team at the University Health Network. Dr. Lupien’s research project showcases Canadian leadership in immunology, genomics and epigenetics and, ultimately, will lead to new treatments to extend survival and quality of life for women diagnosed with triple-negative breast cancer,” said Dr. Stephen Robbins, Scientific Director of the CIHR Institute of Cancer Research.

     About TFRI

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

     

    About CIHR 

    The Canadian Institutes of Health Research (CIHR) is the Government of Canada's health research investment agency. CIHR's mission is to create new scientific knowledge and to enable its translation into improved health, more effective health services and products, and a strengthened health care system for Canadians. Composed of 13 Institutes, CIHR provides leadership and support to more than 13,000 health researchers and trainees across Canada. http://www.cihr-irsc.gc.ca/

     

    For more information contact:

     

    Kelly Curwin, Chief Communications Officer
    Terry Fox Research Institute
    Vancouver BC

    Office: 604-675-8223
    Cell: 778-237-8158
    kcurwin@tfri.ca

     

     


  • 2016 NEW FRONTIERS PROGRAM PROJECT GRANTS COMPETITION RECIPIENT

    by TFRI Editor | Sep 07, 2016

    Dr. LupienNew TFRI project tackling most deadly and aggressive breast cancer from all directions

    Triple-negative breast cancer (TNBC) persists as a deadly form of breast cancer today that lacks effective therapies. Now, a newly formed and funded Terry Fox Research Institute team hopes to employ a four-pronged approach to change the odds for TNBC patients.

    Nearly all patients relapse within five years, and the median duration of survival is six to 12 months after the first metastasis, so there’s a drastic unmet clinical need here,” says Dr. Mathieu
    Lupien, a senior scientist at the Princess Margaret Cancer Centre in Toronto, Ontario. “There’s not necessarily one research route that will solve it all, so we need to be able to tackle the problem taking multiple different approaches.”

     The team is focused on four research areas to enable better outcomes through new precision therapies:

    >Improving immunotherapy treatments
    >Changing tumour metabolism
    >Exploiting epigenetics vulnerabilities
    >Accelerating new treatment discovery through personalized models of patient-derived tumours

    “This is a fabulous team with a strong track record of discoveries made in breast cancer in their respective fields,” he says about his co-investigators. “We have a great synergy, and when we work as a team it goes a whole lot farther than if we work as single units. This team has a lot to offer!”

    The Canadian Institutes of Health Research (CIHR) is partnering with TFRI in the funding of this important research project. As well, the immunotherapy component of the project will be co-led by Dr. Pam Ohashi, who is co-leading a new pan-Canadian project focused on using immunotherapy to improve outcomes for women diagnosed with a lethal form of ovarian cancer.

    Breast cancer is the second leading cause of death of Canadian women, with more than 5,000 dying from the disease each year. Around 20 per cent of these patients are diagnosed with triple negative breast cancer, an extremely heterogeneous disease with no precision therapy options. The disease is more likely to affect women under age 40.

    The project will also generate significant resources in both datasets and personalized TNBC models for the broader research community in Canada, providing long-term benefits to improve patient care through personalized medicine.

    Project Title: Delineating therapeutic opportunities in triple-negative breast cancer
    Project Leader: Dr. Mathieu Lupien, PMCC, UHN
    Investigators: Drs. Cheryl Arrowsmith, Pam Ohashi, Trevor Pugh, Linda Penn, Benjamin Haibe-Kains, David Cescon, Lillian Siu (all PMCC, UHN)
    Award total: $2.25M
    Co-funder: Canadian Institutes of Health Research
    Duration: 2016-2019

    Dr. Mathieu Lupien (PMM)
  • 2016 NEW FRONTIERS PROGRAM PROJECT GRANTS COMPETITION RECIPIENT

    by TFRI Editor | Sep 06, 2016

    From mini-guts to the Hippo Pathway: Shutting down tumour growth in colorectal cancer

    Snapshot of 3d gut organoids 5 - CopyIn order for cancer to grow inside our bodies, it must overcome a series of control mechanisms that are important for tissue growth. One mechanism which is responsible for body organ size is aptly called the “Hippo” pathway.

    “This pathway constrains tissue size, and in cancer this pathway is inactivated, so the ability to control the growth of the tumour is lost,” says senior investigator Dr. Jeff Wrana, based at Toronto’s Lunenfeld-Tanenbaum Research Institute (LTRI) at Mount Sinai Hospital.

     His newly-funded research team, which includes a handful of colleagues based at LTRI, will use their funding to understand how they can intervene and reactivate this pathway to suppress tumour growth.”

     The team is focusing on colorectal cancer, the second leading cause of cancer death in Canada. Roughly one in every 14 people is likely to develop the disease.

     “The Hippo Pathway, the same regenerative pathway that’s so critical in repairing the intestine, is also playing a key role in the initiation of colorectal cancers,” Dr. Wrana says. “So our first focus is on colorectal cancer, and how we can interfere with this pathway using small molecules.”

    The team is divided into three sub-projects:

    Project 1 members will focus on target identification – or identifying ways the Hippo
     pathway can be controlled;

    Project 2 is aiming to identify small molecules and drug-like compounds that can act like inhibitors for the pathway;

    Project 3 will create new therapeutics to treat colorectal cancer at different stages of disease.

     Dr. Wrana says one of the things he’s most excited about is the cutting-edge technology the team will be utilizing. “Our core really is one of the top screening and mass spectrometry centres in the world,” he says. “We can exploit these technologies to do drug screens and do systematic mapping of protein networks and that kind of stuff, and then link it all back to colorectal cancer.”

     Mini-guts, or little tissues derived from stem cells that look like the gut, will also be developed to test new therapeutics. Part of the project will create patient-derived mini guts to match each individual’s genetic background, taking personalized medicine to the next level.

    “It’s an exciting aspect of modern science,” says Dr. Wrana. “We are absolutely elated to receive this grant, and we are so grateful to the Institute, and the critical role that donors play.”

    Project Title: Targeting the Hippo Signaling Network in Cancer
    Project Leader: Dr. Jeff Wrana, Lunenfeld-Tanenbaum Research Institute, Sinai Health System
    Investigators: Helen McNeill, Frank Sicheri, Anne-Claude Gingras, Steve Gallinger, Liliana Attisano
    Award total: $2.25M
    Duration: 2016-2019

    Related Patient Story: 

    Erika Schroedersecker: http://www.tfri.ca/en/OurWork/patient-stories/erika-schroedersecker

    From mini-guts to the Hippo pathway: Shutting down tumour growth in colorectal cancer

    From mini-guts to the Hippo pathway: Shutting down tumour growth in colorectal cancer

  • 2016 NEW FRONTIERS PROGRAM PROJECT GRANTS COMPETITION RECIPIENT

    by TFRI Editor | Sep 06, 2016

    Vancouver-based team will use new funding to continue its world-class research to overcome drug resistance in prostate cancer

    Dr. Martin GleaveTFRI’s Vancouver-based prostate cancer progression team is primed and ready to continue its world-class research on advanced, drug-resistant tumours after receiving a five-year renewal of Terry Fox funding.

    “This project is, in many ways, a continuation of ongoing work we have conducted for the past 15 years to better understand how prostate cancers adapt and evolve, thereby becoming resistant to the various drugs that we use to try and control advanced disease,” says Dr. Martin Gleave. He leads the New Frontiers Terry Fox Program Project Grant’s 20-person multidisciplinary team from the Vancouver Prostate Centre, where he is also the executive director.

    The team has a prolific track record for its success as a leader in developing new therapies to help patients whose cancer becomes resistant:

    > Notably, the anti-clusterin drug OGX-011, which was developed and supported with  earlier funding from the Terry Fox Foundation (among others), is currently being  tested in a Phase III clinical trial. An earlier Phase II study showed a seven-month  gain in survival for patients;

    > The group has also created four other targeted therapeutics, two biomarker  assays, and completed eight Phase I/II trials of novel agents;

    > Therapies that inhibit Hsp27 and ERG, which encode proteins typically mutated in  cancer, are in the works;

    > Their work has been published in more than 430 journal articles and they’ve filed  99 patents.

    With the latest injection of funding, the team will apply more cutting-edge science, such as new genomic technologies and computer-aided drug design, to their existing work. The lab also outlicensed a novel androgen receptor DNA-binding domain inhibitor to Roche, the largest ever from UBC, and will also be leading the first in-man clinical trial of the drug.

    “All of these projects are very cool and hold tremendous potential,” says Dr. Gleave. “Canada is able to hit well above its weight in the global arena, and I think that’s because of strategic funding from the Terry Fox Research Institute, which has been very forward- thinking in helping to bring people with multiple skill sets together to tackle bigger problems in science.”

    Prostate cancer is the third leading cause of cancer-related death in Canadian men, and one of the most common cancers for this demographic.

    Project Title: Targeting the adaptive molecular landscape in castrate-resistant prostate cancer
    Project Leader: Dr. Martin Gleave, Vancouver Prostate Centre, UBC
    Investigators: Ralph Buttyan, Artem Cherkasov, Kim Chi, Colin Collins, Michael Cox, Mads Daugaard, Emma Guns, Christopher Ong, Alan So, Poul Sorensen, Yuzhuo Wang, Amina Zoubeidi (UBC, VPC)
    Award total: $7.5M
    Duration: 2016-2021

    Related Patient Story:

    Denis Petitclerc: http://www.tfri.ca/en/OurWork/patient-stories/denis-petitclerc

    Previously Funded Project: The Terry Fox New Frontiers Program Project Grant in Prostate Cancer Progression (2011-2016).

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