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  • Biology of tumour changes when childhood brain cancer recurs, Canadian study finds

    by User Not Found | Feb 12, 2019

    TORONTO/VANCOUVER – New research co-funded by the Terry Fox Research Institute offers a simple explanation as to why new and experimental treatments fail for children with recurrent medulloblastoma, the most common cancerous brain tumour in children. The study was conducted by The Hospital for Sick Children (SickKids) and the BC Cancer Agency and is part of the Medulloblastoma Advanced Genomics International Consortium (MAGIC) project. The paper is published in the January 13 online edition of Nature.

    Using samples of children’s and mouse models’ medullobastoma tumours, the research team found the biology of tumours at the time of diagnosis had significantly transformed in recurrent medulloblastoma tumours. Their findings suggest that targeted therapies tested on, and found to successfully treat initial untreated tumours in the lab, are ineffective in treating recurrent tumours because the identified targets in the initial tumour are absent in the recurrent tumour. The biology is completely different.  

    Clinical trials testing new drugs for children with brain cancer have generated very few success stories over the past few decades. New, biologically based treatments for childhood brain cancers – the most common type of solid cancer in children – are rare. Medulloblastoma is known to be difficult to successfully treat, and side-effects from current therapies, including chemotherapy, radiation and surgery, can have a devastating impact on a child’s developing central nervous system. Nearly 30 per cent of cases result in a recurrence of the tumour, which is nearly universally fatal.

    Dr. Michael Taylor, co-principal investigator of the study and Neurosurgeon and Senior Scientist at SickKids, explains, “Almost all of the research done to understand the biology of childhood brain cancer, and to identify new drugs that might work, is done using tumour tissue removed at the time of the first surgery, before the children have received any radiotherapy or chemotherapy. Conversely, almost all of the experimental drugs that are identified are then tested in clinical trials that enrol children who have received extensive therapy of their cancer. This work flow is based on the assumption that the biology of the tumour when it is first diagnosed is very similar to the biology of the tumour after it has been treated.”

    Taking a step back from this assumption, Taylor, co-principal investigator Dr. Marco Marra from the BC Cancer Agency, and their Canadian-led research team decided to test its validity. The scientists used whole genome sequencing to test matched pairs of tumour samples from 33 children with medulloblastoma. Each pair included tissue removed at diagnosis (before the child began any form of therapy), and at the time of cancer recurrence (after undergoing therapy). They found a substantial genetic change in the recurrent tumours. They also treated genomic ‘humanized’ mouse models with surgical and radiation therapies, finding a poor overlap (under 5 per cent) between recurrent tumours and untreated diagnostic samples. In both mice and humans, the dominant genetic target at recurrence was different from the one identified at diagnosis.

    “To everyone’s surprise, the biology of the recurrent tumour was vastly different than the pre-treatment tumour, with only about one in 10 mutations found initially still there at recurrence. This massive change in biology offers a simple reason for why new drugs discovered to work in the laboratory on pre-treatment samples do not work when they are tested in children with recurrent tumours – it's like trying to make orange juice out of apples. This simple explanation could change the way we test drugs in children,” says Taylor, who is also Principal Investigator at the Arthur and Sonia Labatt Brain Tumour Research Centre at SickKids and Associate Professor in the Departments of Surgery and Laboratory Medicine and Pathobiology.

    Dr. Marco Marra, Distinguished Scientist at the BC Cancer Agency and Director of Canada's Michael Smith Genome Sciences Centre, adds that recurrent and treatment-resistant tumours should be studied further to identify treatments that may be effective in treating them. “Genomic profiling of treatment-resistant cancers has much to contribute to informing treatment decision- making in medulloblastoma and other cancer types,” says Marra, who is also Professor and Head of the Department of Medical Genetics at the University of British Columbia.

    The study was supported by Genome Canada, Genome British Columbia, Ontario Institute for Cancer Research, Terry Fox Research Institute, Canadian Cancer Society Research Institute, Stand Up to Cancer St. Baldrick’s Dream Team Translational Cancer Research Grant, Pediatric Brain Tumor Foundation, the National Institutes of Health and SickKids Foundation, as well as a number of other generous funders.

  • Terry Fox award helps Ottawa researcher develop next-generation cancer immunovirotherapy

    by User Not Found | Feb 12, 2019

    Ungerechts_web

    What if there was a way to destroy cancer cells and stimulate a patient’s own immune system to attack tumours, while leaving healthy tissues unharmed?

    The Terry Fox Research Institute (TFRI) has awarded Dr. Guy Ungerechts (The Ottawa Hospital and the University of Ottawa) a $450,000 New Investigator grant to develop innovative new treatments to achieve just that. Dr. Ungerechts is part of TFRI’s Canadian Oncolytic Virus Consortium (COVCo), and is mentored by Dr. John Bell, senior scientist at The Ottawa Hospital and the University of Ottawa and COVCo lead investigator. 

    An oncolytic virus works to destroy cancer in multiple ways, explains Dr. Ungerechts, notably by stimulating the immune system and directly killing cancer cells. The team plans to use a modified version of the Measles virus vaccine as an oncolytic “cancer vaccine”, enhancing it with a second virus (the Maraba virus) that will act as a booster.

    The team is already testing a similar strategy in patients in Ottawa, Hamilton, Toronto and Vancouver. However, this trial uses one virus (Maraba) that can replicate and spread throughout the tumour and one that cannot (Adenovirus). This next-generation therapy would use two replicating oncolytic viruses, to hopefully maximize tumour destruction.

    “What we would like to do in the TFRI project is use the Measles virus to mount a great response from the patient’s immune system,” said Dr. Ungerechts, who is trained as a medical oncologist and molecular virologist. “We will inject the virus right into the tumour site so it will replicate in the tumour, stimulate the immune system and hopefully destroy cancer cells.” 

    The Measles virus was chosen for several reasons: it’s already used as an effective vaccine for children, and has an excellent safety profile. Further, early clinical trials run by researchers from the Mayo Clinic, USA have shown impact in patients with different types of cancer.

    Dr. Ungerechts is also exploring approaches to genetically modify the Measles virus to express various immunomodulatory payloads, stimulating the immune system to attack cancer cells specifically. Examples include immune checkpoint inhibitors (anti-PD1/PD-L1-blockade) and bispecific T cell engagers (BITEs).

    Determining which approach is most effective for killing cancer cells and stimulating the immune is an exciting prospect for Dr. Ungerechts. By the end of his three-year award, he hopes the novel treatment will be moved to clinical trials for advanced-stage cancer patients who have run out of options.

    “Immuno-viro-therapy could be a paradigm shift for cancer treatment, but we are still at an early stage of this research, particularly for oncolytic viruses.” Dr. Ungerechts said. “It’s a very promising field right now. This TFRI award means a lot, and I’m more than happy to be one of the lucky people who earned it.”

    “We are very excited to welcome Dr. Ungerechts to our team,” said Dr. Bell, who is also the scientific director of BioCanRx and program director for immuno- and bio-therapeutics at the Ontario Institute for Cancer Research (OICR). “He is a great fit with our group and brings technology and expertise that we truly value. His participation within COVCo will expand our repertoire of therapeutics for testing and diseases that we could focus our team’s expertise and ideas upon.”

    Dr. Ungerechts is also supported by the Ontario Institute for Cancer Research and The Ottawa Hospital Foundation.

    Patients interested in participating in oncolytic virus clinical trials should speak with their own oncologist, and can also consult The Ottawa Hospital website.

    Project Title: Next Generation Cancer Immunovirotherapy: Heterologous oncolytic prime-boost enhanced with select immunomodulators 
    Award: $450,000
    Mentoring Program: The Terry Fox New Frontiers Program Project Grant in Canadian Oncolytic Virus Consortium (2007-2017)
    Mentors/PIs: Dr. John Bell

    About The Terry Fox Research Institute (TFRI)

    Launched in October 2007, The Terry Fox Research Institute is the brainchild of The Terry Fox Foundation and today functions as its research arm. TFRI seeks to improve significantly the outcomes of cancer research for the patient through a highly collaborative, team-oriented, milestone-based approach to research that will enable discoveries to translate quickly into practical solutions for cancer patients worldwide. TFRI collaborates with over 65 cancer hospitals and research organizations across Canada. TFRI headquarters are in Vancouver, BC. www.tfri.ca

    About The Terry Fox Foundation (TFF)

    The Terry Fox Foundation maintains the vision and principles of Terry Fox while raising money for cancer research through the annual Terry Fox Run, Terry’s CAUSE on Campus, National School Run Day and other fundraising initiatives. To date, over $700 million has been raised worldwide for cancer research in Terry Fox's name. The first Terry Fox Run was held in 1981, with The Terry Fox Foundation being created in 1988. Its national headquarters are located in Chilliwack, BC and it has offices in 9 provinces. www.terryfox.org.

    About The Ottawa Hospital

    The Ottawa Hospital is one of Canada’s largest learning and research hospitals with over 1,100 beds, approximately 12,000 staff and an annual budget of over $1.2 billion. Our focus on research and learning helps us develop new and innovative ways to treat patients and improve care. As a multi-campus hospital, affiliated with the University of Ottawa, we deliver specialized care to the Eastern Ontario region, but our techniques and research discoveries are adopted around the world. We engage the community at all levels to support our vision for better patient care. Visit www.ohri.ca for more information about research at The Ottawa Hospital.

    About the University of Ottawa
    The University of Ottawa is home to over 50,000 students, faculty and staff, who live, work and study in both French and English. Our campus is a crossroads of cultures and ideas, where bold minds come together to inspire game-changing ideas. We are one of Canada’s top 10 research universities—our professors and researchers explore new approaches to today’s challenges. One of a handful of Canadian universities ranked among the top 200 in the world, we attract exceptional thinkers and welcome diverse perspectives from across the globe. www.uottawa.ca.

  • Restoring stem cells to a fetal-like state could provide a therapeutic alternative for acute leukemias

    by Peter Mothe | Jan 15, 2019

    GiambraWeng

    Restoring a signaling pathway that is prevalent in fetal stem cells but dormant in adult ones may hold potential as an alterative treatment for T-cell acute lymphoblastic leukemia (T-ALL), an often-deadly type of blood cancer.

    In a study published in Cell Stem Cell (November 2018), a TFRI-funded team led by Vancouver clinician-scientist Dr. Andrew Weng (BC Cancer) describes how they set about using mouse models of T-ALL from two different types of progenitor cells – fetal liver (FL) cells and adult bone marrow (BM) cells – to determine if leukemia had different biological properties at different stages of life.

    “What we discovered is that fetal and adult leukemias behave differently and that these differences are primarily based on the inhibition or activation of two pathways: EZH2 and IGF1,” said Dr. Weng, the paper’s senior author.

    According to Dr. Weng, NOTCH 1-driven autocrine IGF1 signalling is active in FL cells but restrained in adult BM cells due to a process known as EZH2-dependent H3K27 trimethylation. This fundamental biological difference has a huge impact on the aggressiveness of a leukemia as the scientists found that FL cells with active IGF1 signalling had reduced transplantability when compared to BM cells and had less leukemia stem cell activity.

    This observation led them to search for ways to pharmacologically block EZH2-dependent H3K27 trimethylation to restore IGF1 signalling in adult cells, a process that yielded positive results in both mouse models and patient-derived xenografts.

    “We found that enforced IGF1 signaling depletes leukemia stem cells in both mouse and human T-ALL,” said Dr. Weng. “These findings demonstrate that resurrecting dormant fetal programs in adult cells may represent an alternate therapeutic approach in human cancer.”

    Study
    Epigenetic Restoration of Fetal-like IGF1 Signaling Inhibits Leukemia Stem Cell Activity

    Authors
    Vincenzo Giambra, Samuel Gusscott, Deanne Gracias, Raymond Song, Sonya H. Lam, Patrizio Panelli, Kateryna Tyshchenko, Catherine E. Jenkins, Catherine Hoofd, Alireza Lorzadeh, Annaick Carles, Martin Hirst, Connie J. Eaves, and Andrew P. Weng

    Funding
    This study was partially funded by a Terry Fox New Frontiers Program Project Grant in Exploiting Pathogenic Mechanisms in Acute Leukemia for Clinical Translation

  • CEST MRI may be able to measure patient response to chemotherapy within 24 hours after first dosage

    by Peter Mothe | Jan 15, 2019
    Stanisz_Photo

    TFRI-funded researchers based in Toronto have found that a specific type of magnetic resonance imaging (MRI) tool may be able to measure how breast cancer patients respond to chemotherapy within a day of treatment.

    Published in Oncotarget (July 2018), the finding reveals that chemical exchange saturation transfer MRI (CEST MRI) can detect cancer cell death in mice within 24 hours of receiving chemotherapy, much sooner than current methods, which measure changes in tumour size and may take up to six months to reveal if patients effectively respond to treatment.

    There are no clinically used methods now for detecting early tumour responses to therapy. The team sought to explore new tools because current techniques have significant limitations pertaining to reliability, sensitivity, specificity and, in some cases, cost more to use. This tool “does not require injections of exogenous media and could be easily integrated into existing clinical MRI protocols,” state the study authors.

    “This finding offers another non-invasive tool for the early detection of treatment response, which could be used to more quickly identify treatments that do not work in certain patients so they can be switched to another treatment that hopefully works better,” says MRI specialist and lead author Dr. Greg Stanisz, (Sunnybrook Research Institute and University of Toronto).

    The team used an in vivo tumour model of 16 breast cancer xenografts (MDA-MB-231) for this study to differentiate between viable tumours and tumour regions containing cell death on both pre- and post-chemotherapy scans. Their results, based on magnetization transfer ratio cutoffs, showed a trend indicating the maximum cytotoxic effect at 8 to 12 hours after chemotherapy was given. Their results were also similar to patterns found in histological assessments.

    The group is excited about the potential benefit for patients from this work, and now plans to design clinical studies that will test the use of CEST MRI in women with breast cancer.

    Study
    Chemical exchange saturation transfer MRI to assess cell death in breast cancer xenografts at 7T

    Authors
    Jonathan Klein, Wilfred W. Lam, Gregory J. Czarnota and Greg J. Stanisz

    Funding
    This work was supported by a The Terry Fox New Frontiers Program Project Grant in Ultrasound and MRI for Cancer Therapy 



  • New finding suggests that disrupting interaction between MYC and G9a could stop cancer growth

    by Peter Mothe | Jan 15, 2019

    Penn_Image2

    A novel technology has helped a TFRI-funded multidisciplinary research team identify how a key driver of human cancer works, cracking open the possibility for new targets and treatments to stop it in its tracks.

    MYC mutations are present in over half of all cancers, and whenever they occur, cancers are more aggressive, and prognosis is much worse, explains Dr. Linda Penn, a TFRI-funded investigator and molecular oncologist at the Princess Margaret Cancer Centre in Toronto. “Whenever MYC activity is out of control, it's a very nasty beast. In fact, if MYC is overexpressed in a cell, it can drive cancer in that cell, no matter what type of cell it is.”

    But despite three decades of research, scientists have been unsuccessful in identifying drugs that could inhibit it, partly because there was little understanding of how MYC actually worked.

    Now Dr. Penn and her multidisciplinary colleagues are closing this knowledge gap with a new study published in Cancer Cell (November 2018) that explains MYC’s interaction with a protein called G9a. “What we learned is that the interaction of MYC with G9a is extremely important for MYC to drive oncogenesis. This is an important finding because it means that if we figure out how to target G9a, we could basically disable MYC activity,” says Dr. Penn, the study’s senior author.

    An epigenetic regulator, G9a helps determine what bits of the genome are turned off or turned on. The study team found that when it interacts with MYC, it represses specific gene transcription causing cancers to form.

    To make this breakthrough, the team used a novel new technology known as BioID to identify all proteins that interact with MYC.

    “This collaborative effort with this new technology has allowed us to just bust open the cell for the first time and identify all those partner proteins that make up the MYC interactome,” says Dr. Penn. “And G9a isn’t the only one we have identified – there are 350 other proteins that MYC interacts with that can be analyzed as potential targets for the development of anti-cancer drugs.”

    Study
    MYC Interacts with the G9a Histone Methyltransferase to Drive Transcriptional Repression and Tumorigenesis

    Authors
    Tu WB, Shiah YJ, Lourenco C, Mullen PJ, Dingar D, Redel C, Tamachi A, Ba-Alawi W, Aman A, Al-Awar R, Cescon DW, Haibe-Kains B, Arrowsmith CH, Raught B, Boutros PC, Penn LZ

    Funding
    This work was partially supported by a grant to the Terry Fox New Frontiers Program Project Grant in Delineating therapeutic opportunities in triple-negative breast cancer

  • Montreal research team identifies SREBF1 as a new, targetable regulatory pathway in prostate cancer

    by Peter Mothe | Jan 15, 2019

    Giguere_Image

    The discovery of a new pathway for the treatment of castrate-resistant prostate cancer has scientists in Montreal excited about how repurposed and new drugs targeting it may benefit patients.

    In a study published in Molecular Cancer Research (September 2018), the TFRI-funded team led by Dr. Vincent Giguère (Goodman Cancer Research Centre, McGill University) identified a newly discovered downstream effector of the androgen receptor (AR)/mammalian target of rapamycin (mTOR)axis, a pathway known as SREBF1 that was found to be directly responsible for controlling prostate cancer cell metabolism.

    “We found that SREBF1 expression is contingent on the dual activation of the AR/mTOR signaling pathways and is essential in controlling two key metabolic processes in prostate cancer: the balance between usage of citrate for mitochondrial ATP synthesis and de novo lipid synthesis,” explains Dr. Etienne Audet-Walsh, the lead author of the study.

    These two metabolic processes allow prostate cancer cells to gain the energy they need to grow and spread, which is why identifying a pathway that controls them is so important: if it can be inhibited genetically or pharmacologically, then perhaps the cancer cells can be starved to death.  Sterol regulatory element-binding transcription factor 1 (SREBF1) is in fact targetable, making this discovery even more exciting.

    The finding builds on previous groundbreaking work by the team studying cancer metabolism. In 2017, they revealed how the nuclear fraction of mTOR and androgen receptors worked together to facilitate the growth and proliferation of prostate cancer cells. The team has continued to dive deeper into the relationship between mTOR and AR to gain a greater understanding of the metabolic processes involved in tumour proliferation and potential novel therapeutics.

    “Our study has found that pharmacologic inhibition of SREBF1 impairs prostate cancer cell proliferation in vitro and in vivo, and what’s best is that this regulatory pathway can be targeted by several pharmacological approaches already in use to treat other diseases,” says Dr. Giguère. “Our work supports drug-repurposing for the treatment of prostate cancer and thus will potentially lead to the approval of new medications for prostate cancer following appearance of resistance.”

    Study
    SREBF1 Activity Is Regulated by an AR/mTOR Nuclear Axis in Prostate Cancer

    Authors
    Etienne Audet-Walsh, Mathieu Vernier, Tracey Yee, Chloé Laflamme, Susan Li, Yonghong Chen, and Vincent Giguère

    Funding
    This work was partially supported by a grant to the Terry Fox Program Program Grant in Oncometabolism and the Molecular Pathways that Fuel Cancer

  • Study reveals genomic differences between long- and short- term survivors of high-grade serous ovarian cancer, advancing potential for individualized treatments

    by Peter Mothe | Jan 15, 2019

    Pugh_Image
    Trevor Pugh is a TFRI-funded researcher who co-lead the study.

    Researchers may be one step closer to creating personalized treatments for patients with an extremely deadly form of ovarian cancer thanks to a new study by a Toronto group funded by TFRI.

    The study, published in Genome Medicine (October 2018), maps the clinical and genomic differences between two sub-groups of patients with high-grade serous ovarian cancer (HGSOC): those who respond exceptionally well to the standard-of-care treatment of cytoreductive surgery and platinum-based chemotherapy, known as exceptional long-term (LT) survivors, and those who quickly build resistance to it, short-term (ST) survivors.

    “In this pilot study, we sought to identify clinical and molecular factors that distinguish HGSOC patients who share similar clinical characteristics and pathology at diagnosis with exceptional survival outcomes, either LT or ST, through integrated analysis of clinical features, germline variants, somatic genomic alterations, and tumour immune microenvironment,” reads the paper.

    Using samples from 20 LT survivors and 21 ST survivors collected at the Princess Margaret Cancer Centre in Toronto, the team was able to determine several key differences between the groups, including an elevated mutation burden, biallelic inactivation of BRCA1 or BRCA2, and increased CD4+ and CD8+ lymphocytic infiltration in the tumour microenvironment in LT survivors. These findings suggest that exceptional long- or short-term survival is determined by a concert of clinical, molecular, and microenvironment factors.

    The team also found the ESR1-CCDC170 gene fusion present in tumours from two HGSOC patients with extremely short survival, which could point to this fusion as a potential biomarker for treatment resistance and aggressive disease.

    While these findings will now need to be validated using a larger cohort, researchers are hopeful that they will help bring them closer to tailoring treatments for these patients based on their individual genetic and clinical landscapes.

    “Identifying mechanisms involved in the response or resistance to treatment is essential to devising precision treatment plans, and future strategies will likely rely on multiple clinical and immunogenomic factors,” reads the paper. “This analysis of exceptional responders in HGSOC has the potential to contribute to our understanding of the biology of ovarian cancer, with the goal of improving the survival of patients.”

    Study
    Landscape of genomic alterations in high-grade serous ovarian cancer from exceptional long- and short-term survivors

    Authors
    Yang SYC, Lheureux S, Karakasis K, Burnier JV, Bruce JP, Clouthier DL, Danesh A, Quevedo R, Dowar M, Hanna Y, Li T, Lu L, Xu W, Clarke BA, Ohashi PS, Shaw PA, Pugh TJ, Oza AM

    Funding
    This work was supported by a Terry Fox Translational Research Program Grant to iTNT: The Immunotherapy Network.

  • Use of mTOR inhibitors increases efficacy of herpes virus as an oncolytic therapy

    by Peter Mothe | Jan 15, 2019

    Alain_Image


    In recent years, the herpes simplex virus 1 (HSV1) has emerged as one of the most advanced and successful oncolytic viruses. But despite having received approval from the US Food and Drug Administration (FDA) in 2015 for use in melanomas, certain limitations – such as sustained viral replication within tumours – still restrict its efficacy as a successful anti-cancer therapy.

    In this context, a new study published by a team of TFRI-funded researchers based in Ottawa and Montreal could mark the beginning of a new era for the use of HSV1 as a therapeutic option for cancer. The study, published in PLOS Pathogens (August 2018), found that combining HSV1 with mTOR inhibitors (which suppress the Mammalian Target of Rapamycin (mTOR), an important enzyme found to be hyperactive in cancer cells) improves viral replication within tumour cells with dysregulated protein synthesis, boosting the virus’ efficacy.

    “What this study revealed is that adding active-site mTOR inhibitors to cancer cells with dysregulated protein synthesis resulted in an altered cellular state that preferentially benefits the replication of HSV1,” explains Dr. Tommy Alain (University of Ottawa and Children’s Hospital of Eastern Ontario), a viral oncologist and the paper’s senior author. “Such combination could therefore be developed to improve both mTOR- and HSV1-targeted anti-cancer therapies.”

    To reach this conclusion, the team combined active site mTOR inhibitors (asTORi) with a specific variation of HSV1 (HSV1-dICP0) in cancer cells and a mouse mammary cancer xenograft. The combination therapy reduced tumour size of this aggressive syngeneic breast cancer and revealed that cancer cells harboring altered mRNA translation via dysregulated eIF4E/4E-BPs axis can be targeted by the combination of asTORi and HSV1-dICP0.

    According to Dr. Alain, this occurred because the combination therapy promoted viral replication within certain cancer cells, while actively suppressing the virus in normal cells, making the combination therapy a more effective way to specifically target the cancerous cells.

    “Clinicians or oncologists treating patients with either mTOR inhibitors or an oncolytic HSV1 may consider combining the two therapies for improved therapeutic responses, especially if the cancer displays signs of dysregulated protein synthesis,” says Dr. Alain.

    Study
    Active-site mTOR inhibitors augment HSV1-dICP0 infection in cancer cells via dysregulated eIF4E/4E-BP axis

    Authors
    Chadi Zakaria, Polen Sean, Huy-Dung Hoang, Louis-Phillipe Leroux, Margaret Watson, Samuel Tekeste Workenhe, Jaclyn Hearnden, Dana Pearl, Vinh Tai Truong, Nathaniel Robichaud, Akiko Yanagiya, Soroush Tahmasebi, Seyed Mehdi Jafarnejad, Jian-Jun Jia, Adrian Pelin, Jean-Simon Diallo, Fabrice Le Boeuf, John Cameron Bell, Karen Louise Mossman, Tyson Ernst Graber, Maritza Jaramillo, Nahum Sonenberg, Tommy Alain

    Funding
    This work was supported by a The Terry Fox New Frontiers Program Project Grant: Canadian Oncolytic Virus Consortium (COVCo).


  • Pan-Canadian prostate cancer team creates robust resource tool to help clinicians with treatment decision-making

    by Peter Mothe | Jan 15, 2019

    Saad_Image

    A TFRI pan-Canadian research team has created a new biomarker resource that could help personalize treatments for patients with prostate cancer. The resource addresses an urgent need of clinicians for better tools to assist in identifying patients with aggressive versus indolent disease and to guide treatment decision-making.

    The tissue microarray (TMA)-based resource presented in BMC Urology (September 2018) is a robust new platform comprised of 1,512 high-quality radical prostatectomy specimens gathered from biobanks in four provinces across Canada. It has been deemed to be highly representative of the Canadian prostate cancer population, is richly annotated and has a long-term follow-up, making it an extremely valuable resource for researchers around the world looking to validate biomarkers that could help clinicians differentiate aggressive forms of prostate cancer from indolent ones.

    This type of validation is much needed. That’s because some prostate cancers are aggressive and lethal, requiring invasive treatments that often yield life-altering side effects, while others are indolent, meaning treatment may not even be necessary. By using biomarkers to stratify aggressive cases from indolent ones early on, pathologists and clinicians will be able to provide personalized treatments that are effective and that don’t have an unnecessary impact on a patient’s quality of life.

    “There’s an urgent need for biomarkers to help clinicians properly distinguish patients with a higher risk of progression from those with a non-life threatening disease,” said urologist Dr. Fred Saad (Centre de rechercche du Centre hospitalier de l’Université de Montréal), a Montreal-based researcher who leads the TFRI’s Canadian Prostate Cancer Biomarker Network (CPCBN), which conducted the study. “This TMA-based resource is a step towards that and could have a long-term benefit for prostate cancer patients by providing pathologists and clinicians with additional biomarkers that will help patient stratification.”

    The resource is already one of the most robust of its kind in the world, providing insight into the three major endpoints in prostate cancer – biochemical relapse, development of bone metastasis and prostate cancer specific mortality. It will only improve over time as any researcher who uses it will be required to send back results to the CPCBN for the creation of a nomogram that includes the best clinical and pathological biomarkers that could help decision-making in the near future.

    “This platform serves as an invaluable resource for the entire prostate cancer research community, accelerating breakthroughs in PC research, and supporting the establishment of nomograms to predict patient progression,” said Dr. Saad.

    The CPCBN project was co-funded by the Canadian Partnership Against Cancer (CPAC).

    Study
    The Terry Fox Research Institute Canadian Prostate Cancer Biomarker Network: an analysis of a pan-Canadian multi-center cohort for biomarker validation

    Authors
    Véronique Ouellet, Armen Aprikian, Alain Bergeron, Fadi Brimo, Robert G. Bristow, Simone Chevalier, Darrel Drachenberg, Ladan Fazli, Neil E. Fleshner, Martin Gleave, Pierre Karakiewicz, Laurence Klotz, Louis Lacombe, Jean-Baptiste Lattouf, Theodorus van der Kwast, Jeremy A. Squire, Mathieu Latour, Dominique Trudel, Anne-Marie Mes-Masson and Fred Saad

    Funding
    This work was supported by funding from TFRI and CPAC  to the Terry Fox Translational Research Program titled Biomarker-Driven Management of Prostate Cancer Phase II


  • Study shows benefit of vascular normalization in OV therapy for advanced epithelial ovarian cancer

    by Peter Mothe | Jan 15, 2019
    Bridle_Image

    From left to right: Drs. Byram Bridle, Jim Petrik and Sarah Wootton (Photo by Karen Mantel, Ontario Veterinary College)


    Virologists studying the use of viruses to treat cancer have long seen acute vascular shutdown as a positive response to oncolytic virus (OV) therapy. This process, which is characterized by the drastic reduction of blood flow to a tumour after treatment, was believed to make OV treatment more effective by increasing oxygen starvation in cancer cells and sequestering the viruses within the tumours.

    Now a team of scientists partially funded by the TFRI is challenging this paradigm after finding that vascular normalization – rather than shutdown – leads to more effective OV therapy. These findings, which were published in Clinical Cancer Research (September 2018), could open the door to improving the use of OVs for advanced epithelial ovarian cancer (EOC).

    “Our research demonstrates that having a tumour with normal blood vessels, what we call vascular normalization, improves the efficacy of oncolytic viruses by allowing cells of the immune system such as natural killer cells, T cells and antibody-producing B cells to traffic efficiently into the tumour after treatment with the virus, which leads to a superior therapy,” said Dr. Byram Bridle (University of Guelph), a viral immunologist and TFRI New Investigator who co-led the study.

    To reach this conclusion, Dr. Bridle and colleagues created a novel therapy that combined a drug named 3TSR used to normalize tumour vasculature, with a known oncolytic virus named Newcastle Disease Virus, known for its effectiveness in gynecological malignancies. Their hope was that the combination therapy would make tumours more permeable and reduce hypoxia, which in turn would enhance the uptake of the virus within the tumour and subsequent trafficking of effector leukocytes.

    To test this theory the combination therapy was used in a mouse model of EOC with extremely positive results: primary tumour size was reduced, and a significant decrease was seen in the number of secondary lesions. In fact, according the paper, 50 per cent of the mice used in the study were completely devoid of visible secondary lesions, which is an extremely promising result, as secondary lesions are the main cause of death for women with EOC. 

    These observations represent a paradigm-changing approach to oncolytic virotherapy, and have spurred the team to start looking for ways to move the combination therapy forward for testing in patients.

    “These results suggest that our therapy holds substantial potential for improving clinical outcomes for women diagnosed with highly fatal advanced-stage ovarian cancers,” said Dr. Bridle. "We intend to translate this approach into a clinical trial in women with this deadly condition and hope to explore the potential to use this approach to improve the treatments for other cancers.”

    Study
    Combining Vascular Normalization with an Oncolytic Virus Enhances Immunotherapy in a Preclinical Model of Advanced Stage Ovarian Cancer

    Authors
    Kathy Matuszewska, Lisa A. Santry, Jacob P. van Vloten, Amanda WK Au Yeung, Pierre P. Major, Jack Lawler, Sarah K. Wootton, Byram W. Bridle, Jim Petrik

    Funding
    This work was partially supported by a Terry Fox New Investigator Award to Dr. Byram Bridle for Development of Cutting-Edge Biotherapies for the Treatment of Bone Cancers.

     

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