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  • Canadian leaders in tumour hypoxia shed light on the role of mTOR signalling in prostate cancer development

    by TFRI Admin | May 01, 2018
    Istock prostatecancer

    More findings from TFRI’s prestigious hypoxia team are continuing to change the cancer research landscape when it comes to understanding the role of the mTOR signalling pathway in the development and aggressiveness of prostate cancer.

    The group’s latest study, led by Dr. Brad Wouters (Princess Margaret Cancer Centre, University Health Network, Toronto) and published in Molecular Cancer Research (February 2018), highlights two key findings. The first is that the mTOR targets 4E-BP1 and 4E-BP2 proteins play a tumour suppressive function even in the context of constitutive PI3K activation driven by PTEN loss in prostate cancer. Their deletion accelerates tumorigenesis, or the production of tumours. The mTOR signalling pathway is a central regulator of protein synthesis and cellular metabolism that responds to the amount of energy, nutrients, oxygen, and growth factors available. The new study demonstrates it retains aspects of this role even in the case of its deregulation.

    The second key finding is that these same two proteins, and the mTOR pathway, play a key role in the survival of hypoxic cells in these tumours. Patients respond poorly to treatment if their tumours are low in oxygen (hypoxic), and these tumours are more likely to grow and spread aggressively. The ability to restrain mTOR signalling during hypoxia, even in the context of upstream PI3K activation driven by PTEN loss, is essential for the survival of hypoxic cells. Thus, despite the more rapid tumour development in mice lacking these genes, the tumours that develop have lower levels of hypoxia.

    The findings of the present study shed light on key upstream pathways that regulate hypoxia tolerance and thus the establishment of aggressive tumours in prostate cancer. Targeting the pathways that regulate mTOR activation, which is a common strategy in many cancers, may thus influence the formation of therapy resistant and aggressive hypoxic cells.

    Prostate cancer is the most common type of cancer affecting Canadian men, and is the third leading cause of death amongst this demographic.

    Study: The mTOR Targets 4E-BP1/2 Restrain Tumor Growth and Promote Hypoxia Tolerance in PTEN-driven Prostate Cancer

    Authors:
    Mei Ding, Theodorus H. Van der Kwast, Ravi N. Vellanki, Warren D. Foltz, Trevor D. McKee, Nahum Sonenberg, Pier P. Pandolfi, Marianne Koritzinsky, and Bradly G.Wouters.

    Funding: This study was partially funded by a long-term grant from The Terry Fox Research Institute.

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  • Schedule announced for Atlantic Node's Workshop on "The Many Ways to Science"

    by TFRI Admin | Apr 25, 2018

    WorkshopBanner

    TFRI's Atlantic Node and the Beatrice Hunter Cancer Research Institute (BHCRI) will be holding a joint workshop on Friday, May 25 for researchers and students in Atlantic Canada. The subject of the workshop will be "The Many Ways to Science," and will include sessions such as "Tips on the Transition into Industry" and "Alternative Careers in Science," among others.  

    According to the event page, the workshop "was developed to enhance the training of cancer research trainees, but with presentations of interest to anyone in the field of cancer research."

    This year's event will be held at the Collaborative Health Education Building (CHEB) (Room C170) in Halifax, NS. Registration starts at 8:30.

    The event's schedule can be found here. For more information, click here
     





  • TFRI New Investigator searches for follicular lymphoma subtypes to guide patient management

    by TFRI Admin | Apr 06, 2018
    Kridel,R_UHN3181


    One of the most frustrating parts of Dr. Robert Kridel’s work is not being able to tell patients diagnosed with follicular lymphoma if they will respond well to treatment or not – a reality he hopes to change through research during his three-year, $450,000 TFRI New Investigator Award.

    “We know that not every patient does the same during treatment: some do well with minimal therapy, some require much more intensive therapy, and some don’t respond and ultimately die from this disease,” says Dr. Kridel, a clinician-scientist based at Princess Margaret Cancer Centre. “If we could determine up front which patients were higher risk we might be able to adapt our treatment, and hopefully improve outcomes for patients.”

    Around 2,500 Canadians will be diagnosed with follicular lymphoma this year, and all these individuals will receive the same cancer treatment. Patient outcomes for this largely incurable disease remain variable: some remain cancer-free for a decade or more, while others experience rapid disease progression and poor outcome.

    Dr. Kridel is working with a team of lymphoma researchers across Canada to accrue and genetically analyze 200 patient tumour samples to identify different subtypes of the disease. The group has already discovered that patients expressing a gene called FOXP1 have a strikingly different outcome post-treatment than patients without the gene.

    “Having this preliminary data in hand makes me quite confident we’ll be successful in identifying differences between patients that are really meaningful, and guide patient management,” Dr. Kridel notes. “The most exciting aspect is that in a few years we might be able to change the way we treat patients by identifying molecular subtypes of follicular lymphoma that are different based on biology and outcome.”

    Dr. Joseph Connors, clinical director of Vancouver’s Centre for Lymphoid Cancer at BC Cancer, is Dr. Kridel’s mentor for the duration of the award.

    “[Dr. Kridel] is a diligent, thorough and meticulous researcher and has built well on his prior clinical and academic experience to prepare for a very productive career in academic medicine,” says Dr. Connors. “I am confident he will become a solid contributor within the community of lymphoid cancer researchers and am delighted his career is off to such a promising start.”

    The opportunity to collaborate with leading lymphoid cancer researchers such as Dr. Connors is one of the most valuable aspects of the New Investigator Award, Dr. Kridel adds.

    “We are always much stronger working together than against each other in science,” he says. “This is the kind of project no single group can do, and it’s typically the effort of teams working together across Canada. We hope our findings will have a meaningful impact on patient lives.” 

    Project Title: Dissecting Biological Heterogeneity in Follicular Lymphoma into Clinically Relevant Molecular Subtypes

    Award: $450,000 over three years

    Mentoring Program: The Terry Fox New Frontiers Program Project Grant in Overcoming Treatment Failure in Lymphoid Cancers (2016-2021)

     
  • Terry Fox Research Institute awards prestigious grant to help Manitoba cancer researcher tackle deadly brain cancer

    by TFRI Admin | Mar 07, 2018

    SachinWINNIPEG—Brain cancer research in Manitoba has received a boost with news that a local scientist has won a prestigious cancer research award from the Terry Fox Research Institute.

    Dr. Sachin Katyal, a researcher at CancerCare Manitoba and the University of Manitoba, is the first researcher in Manitoba to receive the $450,000 Terry Fox New Investigator award for his “quick-to-clinic” personalized medicine approach to better treat patients with glioblastoma multiforme (GBM).

    “Everyone’s so excited Manitoba has won a Terry Fox Research Institute award, especially because this province was Terry’s birthplace,” says Dr. Katyal. “Glioblastoma is a pretty insidious disease and is almost like a death sentence -- it’s got fairly grim statistics, and my goal is to change that.”

    He will use his award to analyze resistant brain cancer tumour cells to determine what DNA-damaging enzyme repair proteins are allowing cancer cells to survive following chemotherapy and radiation treatments.

    The project’s findings will have the potential to help people like Manitoban Lawrence Traa, who was diagnosed with glioblastoma more than five years ago. Having a Terry Fox Research Institute project funded in his province is very exciting, he says, both for himself and for future brain cancer patients.  

    “One of the toughest things for glioblastoma patients to come to terms with is that you may die from the disease,” says Traa. “When we hear about research like this being done in Manitoba, it brings us hope.”

    Dr. Victor Ling, TFRI president and scientific director, is pleased to see the three-year award go to a Manitoba researcher. “These awards are given to promising new cancer clinicians and scientists who represent the future of cancer research. The Terry Fox Research Institute funds several major projects aiming to improve outcomes for glioblastoma patients, and we are pleased to support Dr. Katyal’s work in DNA repair to help find cures for this disease.”

    “This research funding and the partnership among the Terry Fox Research Institute, CancerCare Manitoba and the University of Manitoba, ensures the continuation of transformational research that improves patients lives in Manitoba,” adds Dr. Digvir S. Jayas, vice-president (research) and Distinguished Professor at the University of Manitoba.

    “Through this New Investigator award, Dr. Katyal will be able to network with brain cancer researchers across the country with the potential to impact brain cancer patients,” says Dr. Spencer Gibson, Head of Cell Biology at CancerCare Manitoba’s Research Institute and TFRI Prairie Node Lead.

    More than 2,500 Canadians are diagnosed with brain cancer each year, and GBM is the most common -- and aggressive tumour. [Note: In October 2017, Tragically Hip band member Gord Downie died of this disease.]

    NOTE: More information about Dr. Katyal’s research is available online at:http://www.tfri.ca/en/dr-sachin-katyal

    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 more than 80 cancer hospitals and research organizations across Canada. TFRI headquarters are in Vancouver, B.C. For more information please visit www.tfri.ca and follow us on Twitter (@tfri_research).

     

  • Canadian pancreatic cancer research team provides personalized medicine, new hope to patients

    by TFRI Admin | Mar 06, 2018
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    (From top left to bottom right: Drs. Daniel Renouf, Jennifer Knox, Steven Gallinger, George Zogopoulos, David Schaeffer,, and Oliver Bathe). 

    VANCOUVER – Canadian pancreatic cancer researchers are joining forces under a Terry Fox initiative bringing new hope for patients with this deadly disease.

    “For many years it’s been hopeless from a patient perspective, and we are hoping to help shift this,” says Dr. Daniel Renouf (BC Cancer, University of British Columbia) who, along with Dr. David Schaeffer (UBC, Vancouver General Hospital), is leading a $5-million pan-Canadian, precision medicine initiative recently funded by the Terry Fox Research Institute.

    A lack of early detection tests. Few known symptoms. Very limited treatment options. No known biomarkers that can be used to direct therapy.  These are among the clinical challenges team EPPIC, short for Enhanced Pancreatic Cancer Profiling for Individualized Care, is tackling over the next five years to improve personalized treatments for patients with pancreatic ductal adenocarcinoma (PDAC), a disease with just a nine per cent five-year survival rate.

    “Our project focuses on metastatic cancer versus surgically resectable primary tumours, because this is the clinical problem we see most often,” says Dr. Schaeffer, noting a priority is to discern if the metastatic and primary tumour differ in their genetic make-up. Four out of five patients have metastatic cancer at the time of diagnosis and most will succumb within a year.

    Patients are very keen to participate in the research study. “My push is to keep the support coming for the research, and to bring hope to other pancreatic cancer patients. This is a disease that needs more hope,” says Susan Stewart, 57, a North Vancouver resident who was diagnosed with Stage IV terminal pancreatic cancer in January 2017. She was enrolled immediately in EPPIC as well as a clinical trial where she received an experimental therapy. Although it is early days yet, her results today are promising.  Her pancreatic cancer tumour is no longer visible on CT scans, and the metastatic cancer on her liver has shrunk considerably. Her doctors are using the EPPIC results to try and understand why her tumour has had such an incredible response to the experimental treatment.

    The EPPIC team aims to sequence metastatic pancreatic tumours of 400 patients in Quebec, Ontario, Alberta and British Columbia.  They hope to improve understanding of pancreatic cancer biology to individualize treatment strategies, and to facilitate the development of new treatment options. 

    This project is currently under way in Toronto and Vancouver, through two clinical trials (COMPASS and PanGen), and will be expanded shortly to include eligible patients in Kingston, Ottawa, Calgary, and Edmonton. The Montreal site opens this week. Genomic sequencing and bioinformatics analyses of patient tumours will be conducted at the Ontario Institute for Cancer Research (OICR) and the BC Cancer Genome Sciences Centre.

    The team will also store and analyze the genomic and clinical data collected in a knowledge bank that will be shared by Canadian and international researchers seeking ways to improve treatment.  The bank will be the first of its kind in Canada.

    Dr. Victor Ling, TFRI president and scientific director, is thrilled TFRI is funding this high-calibre precision medicine team to tackle such a hard-to-treat cancer. “Pancreatic cancer research has been historically underfunded, and we are very excited to be expanding such a successful personalized medicine project to patients across Canada.  We hope precision medicine may hold the key to finding better treatments for this incurable disease.”

    EPPIC’s multidisciplinary team comprises clinicians and scientists from BC Cancer, Vancouver Coastal Health Research Institute, University of British Columbia, University of Calgary, University of Alberta, Princess Margaret Cancer Centre, University Health Network, OICR, McGill University Health Centre (MUHC) and the Research Institute of MUHC, Centre hospitalier de l’Université de Montréal, Queen’s University and the Ottawa Hospital.

    In addition to Drs. Renouf and Schaeffer, other principal investigators of EPPIC and the COMPASS and PanGen trials are: Dr. Jennifer Knox and Steven Gallinger (Princess Margaret Cancer Centre/UHN/ OICR), Dr. George Zogopoulos (MUHC/Research Institute of MUHC/McGill University), and Dr. Oliver Bathe (Tom Baker Cancer Center, University of Calgary). Many of the team’s investigators are members of PancOne™, an initiative of Pancreatic Cancer Canada (PCC).

    TFRI’s investment in EPPIC also builds on funding from BC Cancer Foundation, OICR, Princess Margaret Cancer Foundation, PCC and VGH and UBC Hospital Foundation.

    Read the story from McGill University Health Centre here

    Patient Eligibility

    EPPIC is for patients with advanced pancreas adenocarcinoma who have not yet started their first-line chemotherapy. Their oncologist can potentially access the trials by contacting the groups directly. The trial information can be found online by their oncologist at: 

    COMPASS trial: https://www.clinicaltrials.gov/ct2/show/NCT02750657?term=02750657&rank=1  

    PANGEN trial:  https://www.clinicaltrials.gov/ct2/show/NCT02869802?term=02869802&rank=1


    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 more than 80 cancer hospitals and research organizations across Canada. TFRI headquarters are in Vancouver, B.C. For more information please visit www.tfri.ca and follow us on Twitter (@tfri_research).

    Media Contacts

    Kelly Curwin, 604-675-8223; 778-237-8158 (cell) kcurwin@tfri.ca

    EPPIC BACKGROUNDER

    • Pancreatic cancer is the fourth most common cause of cancer-related death in Canada, and affects 5,500 patients a year. In Canada, cancer pancreatic rates are projected to double by 2030.

    • Eighty per cent of patients have metastatic cancer at the time of diagnosis, yet the majority of pancreatic cancer research is only done on the primary tumour.

    • In the United States, pancreatic cancer has just surpassed breast cancer in terms of fatality to become the third most common cause of cancer-related deaths.

    • EPPIC will use an “omics” approach to help advance progress in precision medicine for these patients which will include a detailed molecular analysis of their tumours. In addition, the team will examine each patient’s tumour(s) genome, transcriptome, proteome and metabolome.

    • The team hopes to identify subtypes of the disease based on the above analyses as well as predictive signatures and biomarkers to help individualize treatment, diagnose the disease earlier, and better manage treatment and treatment response.

    • Over the course of the study, the team hopes outcomes will be improved by guiding patients into specific clinical trials in real time.

    • Patients are already enrolled in two sites currently operating and these trials will be expanded to the other identified study sites:

      • The COMPASS trial operates at the Princess Margaret in Toronto and is funded by the Ontario Institute for Cancer Research and Pancreatic Cancer Canada (PCC) NB: Early results from this trial have been positive in demonstrating that sequencing can be performed in a clinical setting and results delivered within a clinically relevant time frame to help guide individual patient treatment.

      • The PanGen trial operates at BC Cancer in Vancouver as part of the Personalized Oncogenomics Program and has been/ is funded by BC Cancer Foundation and PCC.

  • Therapeutic target EZH2 discovered for aggressive, untreatable ovarian cancer affecting young women

    by TFRI Admin | Feb 15, 2018

    Dr. Hunstman

    A Vancouver team led by TFRI-funded investigator Dr. David Huntsman has discovered an important therapeutic target for treating small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). This is a rare, but extremely lethal, ovarian cancer in young women with no effective treatment.

    The present study, published in The Journal of Pathology (June 2017), suggests that SCCOHT tumour cells need the activity of an enzyme called EZH2 for their survival. This enzyme adds methyl groups to the dedicated site of histones, a group of proteins that maintain the proper structure of DNA, and thereby controls which genes to turn on or off.

    Two EZH2 inhibitors (GSK126 and EPZ-6438), in various trials, displayed robust pre-clinical activities against SCCOHT tumour, and are therapeutic targets with the potential to help patients living with this disease. The median age of diagnosis is 24; most women succumb within two years.

    Further, the synthetic lethality between the deficiencies in a multi-protein complex called SWI/SNF chromatin remodeling complex and EZH2 inhibition has been proposed. The present study provided solid evidence supporting this notion in the context of a rare ovarian cancer that is fully driven by complete loss of the enzymatic activity of SWI/SNF complex. The findings also suggest that the deficiency of SWI/SNF complex alone is not sufficient to predict cellular sensitivity to EZH2 inhibition and the cellular context does play an important role.

    Looking forward, the team is working to identify "molecular markers" to predict the response of SCCOHT tumours to EZH2 inhibitors. By seeing which markers are present in patients, researchers can determine the SCCOHT patients that will benefit from the treatment. One of the biggest risks of treating cancer patients with a single drug is the almost inevitable development of resistance to that drug. With this in mind, the group will develop strategies that can improve the efficacy of EZH2 inhibitor treatment alone.

    Study: The histone methyltransferase EZH2 is a therapeutic target in small cell carcinoma of the ovary, hypercalcaemic type.

    Authors: Yemin Wang, Shary Yuting Chen, Anthony N Karnezis, Shane Colborne, Nancy Dos Santos, Jessica D Lang, William PD Hendricks, Krystal A Orlando, Damian Yap, Friedrich Kommoss, Marcel B Bally, Gregg B Morin, Jeffrey M Trent, Bernard E Weissman and David G Huntsman.

    Funding: This study was funded in part by the Terry Fox Research Institute’s New Frontiers Program Project Grant in the genomics of forme fruste tumours; new vistas on cancer biology and treatment.

  • Made-in-Canada model for detecting lung cancer saves lives, is a world leader

    by TFRI Admin | Feb 15, 2018

    Dr. Lam Picture

    A pan-Canadian TFRI team of cancer researchers has developed a predictive model for detecting early-stage lung cancer in high-risk individuals with significantly greater accuracy than other leading models. This study suggests the team’s innovative approach could be considered for use in lung cancer screening programs both in Canada and around the world.

    The results, highlighted in a study published in The Lancet Oncology (Oct. 17, 2017), were also presented at the 18th World Conference on Lung Cancer in Japan by co-principal investigator Dr. Stephen Lam (chair of British Columbia’s Provincial Lung Tumour Group at BC Cancer and a professor of medicine at the University of British Columbia).

    The Pan-Can Lung Cancer Risk-Prediction Model – which is used to determine which individuals should undergo annual CT screening to detect early-stage lung cancer – outperformed comparable models such as The National Lung Screening Trial (led by the National Cancer Institute in the U.S.). The Pan Can Model diagnosed lung cancer in 6.5 per cent of people screened with a follow-up of five years, compared to the four per cent of cases found by the National Lung Screening Trial over a longer term (6.5 years). Further, 77 per cent of the lung tumours diagnosed with the Pan Can Model were caught in early stages, when the cancer is potentially curable, compared to 57 per cent in the NLST study.

    Currently, both the U.S. and Canadian lung cancer screening guidelines are based on age and smoking history. One of the main advantages of the Pan Can Model is it uses a risk prediction tool that looks at numerous additional variables: sex, family history of lung cancer, chronic obstructive pulmonary disease, educational level and body mass index. The TFRI Pan-Canadian Early Lung Cancer Detection Study was expanded in 2017 to examine factors such as genetics and air pollution in lung cancer risk.

    Lung cancer is the most common cause of cancer death around the world with one of the worst survival rates, yet if caught early enough it can be cured in 70 per cent of cases. An accurate predictive model to select candidates who would benefit from CT screening is crucial. The Pan Can Model was developed with $8.4-million support from TFRI and The Canadian Partnership Against Cancer. 

    Study: Participant selection for lung cancer screening by risk modelling (the Pan-Canadian Early Detection of Lung Cancer [PanCan] study): a single-arm, prospective study.

    Authors: Martin C Tammemagi, Heidi Schmidt, Simon Martel, Annette McWilliams, John R Goffin, Michael R Johnston, Garth Nicholas, Alain Tremblay, Rick Bhatia, Geoffrey Liu, Kam Soghrati, Kazuhiro Yasufuku, David M Hwang, Francis Laberge, Michel Gingras, Sergio Pasian, Christian Couture, John R Mayo, Paola V Nasute Fauerbach, Sukhinder Atkar-Khattra, Stuart J Peacock, Sonya Cressman, Diana Ionescu, John C English, Richard J Finley, John Yee, Serge Puksa, Lori Stewart, Scott Tsai, Ehsan Haider, Colm Boylan, Jean-Claude Cutz, Daria Manos, Zhaolin Xu, Glenwood D Goss, Jean M Seely, Kayvan Amjadi, Harmanjatinder S Sekhon, Paul Burrowes, Paul MacEachern, Stefan Urbanski, Don D Sin, Wan C Tan, Natasha B Leighl, Frances A Shepherd, William K Evans, Ming-Sound Tsao, Stephen Lam, for the Pan Can Study Team*

    Funding: Terry Fox Research Institute and Canadian Partnership Against Cancer

  • Nuclear mTOR acts as a transcriptional regulator of metabolism in prostate cancer, groundbreaking study finds

    by TFRI Admin | Feb 15, 2018

    Giguere_TFRI_Figure

    A recent study by TFRI’s cancer metabolism group suggests nuclear mTOR (a kinase) also works as a transcriptional regulator of metabolism in the proliferation of prostate cancer. Their findings underscore a shift in our understanding of the androgen receptor (AR) as the master transcriptional regulator of metabolism in prostate cancer. 

    Dr. Vincent Giguère (McGill University) is the corresponding author of an important Genes and Development paper (August 2017), which sheds light on how prostate cancer develops, survives, and grows. Results showed that mTOR, a regulator of cellular metabolism well-known for its activity in the cytoplasm, also works in the nucleus to directly affect the expression of metabolic genes.

    Their paper suggests mTOR co-operates directly with the androgen receptor to regulate the expression of these genes. Together, the combined action of nuclear mTOR and the AR reprograms the metabolism of prostate cancer cells to favour their growth and proliferation. The team’s findings have brought a new understanding to the molecular mechanisms and the factors involved in promoting prostate cancer cell growth via alteration of their metabolism.

    The team also successfully identified an mTOR-dependent gene signature which could help predict recurrence in prostate cancer patients. Prostate cancer is the third leading cause of cancer-related death in Canadian men, and one of the most common cancers for this demographic.

    This knowledge will benefit the development of future combinatorial therapies against both mTOR and AR to treat prostate cancer. Currently, drugs targeting mTOR have not been an effective therapy for prostate cancer. The present paper suggests this could be because they target the cytoplasmic function of mTOR instead of the nuclear function.

    Importantly, the present study covers the whole spectrum of cancer research, from basic mechanisms of gene regulation to the validation of these findings in gene expression data sets obtained from patient materials, as well as the demonstration that the activity of these factors can be targeted by drugs currently in use in the clinic.

    Study: Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

    Authors: Étienne Audet-Walsh, Catherine R Dufour, Tracey Yee, Fatima Z Zouanat, Ming Yan, Georges Kalloghlian, Mathieu Vernier, Maxime Caron, Guillaume Bourque, Eleonora Scarlata, Lucie Hamel, Fadi Brimo, Armen G Aprikian, Jacques Lapointe, Simone Chevalier, and Vincent Giguère

    Funding: This work was supported in part by a Terry Fox Research Institute New Frontiers Program Project Grant in oncometabolism and the molecular pathways that fuel cancer.

  • Vanadium compounds enhance efficacy of oncolytic viruses when used in combination therapy

    by TFRI Admin | Feb 15, 2018

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    A new class of compounds is generating excitement for its ability to enhance the efficacy of oncolytic viruses (OVs) and to stimulate the immune response against tumours when used in combination therapy.

    A recent paper published in Molecular Therapy by the TFRI-funded Canadian Oncolytic Virus Consortium (COVCo) has shown the ability of vanadium compounds (immuno-modulating, small molecule protein tyrosine phosphatase inhibitors) to improve the efficacy of OVs in cancer treatment. OV therapy – using viruses to stimulate a patient’s own immune system to kill cancer without damaging normal cells – can be very effective, yet some patients don’t respond to OVs alone.

    The present study, led by Dr. Jean-Simon Diallo (Ottawa Hospital Research Institute), showed that combining vanadium compounds with OVs maximized viral oncolysis and systemic anticancer immunity. Importantly, this was true even in cases where the models were refractory to the drug and the OV alone – a finding that could potentially bring hope to patients who face similar challenges.

    Further, the vanadium compounds were able to reverse a signal that would normally lead the tumour to raise its defenses against the virus into one that alarms the immune system towards the presence of the tumour. This occurred when the vanadate inhibited the Type I interferon response and potentiated a pro-inflammatory response via Type II interferon. Notably, the study showed that vanadate preferentially increased the growth of the virus in tumour cores with no impact on normal tissues.

    While no other groups have explored vanadium in combination with oncolytic viruses, the compound has been previously used in clinical trials as an anti-diabetic medication. While it was found to be safe, it did not elicit the desired effect for diabetes treatment and was dropped. The COVCo group is now benefitting from the existing knowledge of vanadium, and hopes to soon bring their groundbreaking pre-clinical findings into clinical trials to continue the development of improved immunotherapy treatments for cancer.

    Study: Multi-modal Potentiation of Oncolytic Virotherapy by Vanadium Compounds

    Authors: Mohammed Selman, Christopher Rousso, Anabel Bergeron, Hwan Hee Son, Ramya Krishnan, Nader A. El-Sayes, Oliver Varette, Andrew Chen, Fabrice Le Boeuf, Fanny Tzelepis, John C. Bell, Debbie C. Crans, and Jean-Simon Diallo.

    Funding: This paper was supported in part by grants to J.S.D. and J.C.B. from the Terry Fox Research Institute. 

  • Ultrasound-stimulated microbubbles enhance radiation effect on prostate cancer cells

    by TFRI Admin | Feb 15, 2018

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    What if there was a way to make cancer cells more susceptible to radiation therapy without damaging healthy cells? New findings from Toronto researchers have shown ultrasound- stimulated microbubbles is a novel type of treatment that may achieve just that.   

    Dr. Gregory Czarnota’s cancer imaging team at Sunnybrook Health Sciences Centre conducted the first study investigating the UGT8 signalling pathway in prostate cancer and found it plays an important role in how tumours respond to ultrasound-stimulated microbubble-enhanced radiation treatment.

    The findings, published in PLOS One (July 17), showed that the down-regulation of UDP glycosyltransferase 8 (UGT8) resulted in more cell death signalling and a greater enhancement of radiation effect when vascular disruption takes place by using ultrasound-stimulated microbubbles. Microbubbles are 1 to 8 μm diameter bubbles comprised of a gas core and stabilized by a protein shell or thin lipid.

    The team carried out experiments both in vitro in cells and tumours in vivo to examine the role of UGT8 in responses to prostate cancer tumours exposed to the ultrasound-stimulated microbubble radiation therapy. The genetically modified prostate cancer cells were treated with either radiation or the ultrasound microbubbles treatment, or a combination of both. The results showed that in cells where UGT8 was down-regulated more cancer cells were destroyed compared to when UGT8 was up-regulated or not regulated at all.

    Further, xenograft tumours generated from stably transfected prostate cancer cells were also treated with either radiation alone or the ultrasound microbubbles treatment, or in combination. Again, there was more cell death in cells with down-regulated UGT8 compared to control tumours and up-regulated UGT8. 

    The study suggests that down-regulating UGT8 leads to increased ceramide levels (a favoured biochemical mechanism leading to endothelial cell death), which creates more cell death signalling. This in turn allows the effects of radiation to be enhanced when the ultrasound-stimulated microbubbles create vascular disruption. Tumour cell death is most efficient when endothelial cell death results in microvascular deterioration. Using ultra-sound activated microbubbles in combination with a specific gene therapy could be a novel, cutting-edge form of cancer therapy that may benefit patients in the future.

    Study: Microbubble-based enhancement of radiation effect: Role of cell membrane ceramide metabolism

    Authors: Azza Al-Mahrouki, Anoja Giles, Amr Hashim, Hyunjung Christina Kim, Ahmad El-Falou, Dean Rowe-Magnus, Golnaz Farhat, Gregory J Czarnota

    Funding: This study was funded in part by a Terry Fox New Frontiers Project Program grant in ultrasound and MRI for cancer therapy.

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