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  • 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

    diallo322x214

    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.

  • Study finds mitochondrial mutations drive prostate cancer aggression

    by TFRI Admin | Feb 15, 2018

    F0202638-Prostate_cancer_cells,_illustration-SPL

    While nuclear mutations are widely acknowledged as a driver of cancer tumours, the role of maternally inherited mitochondrial genome mutations has not been extensively explored – but now a paper from a prolific TFRI-funded team has suggested an important interplay between the two mutations when it comes to prostate cancer tumours.

    The study was recently published in Nature Communications and spearheaded by Drs. Julia Hopkins, Paul Boutros (Ontario Institute for Cancer Research) and Dr. Robert Bristow (formerly with Princess Margaret Cancer Centre). The human genome consists of two genomes – the nuclear and mitochondria – although the nuclear genome is the predominant focus in most cancer research. The present study took a unique approach, analyzing the mitochondrial genomes of 384 localized prostate tumours and identifying numerous mitochondrial single-nucleotide variants (mtSNVs).

    The results were significant: the mitochondrial genomes of prostate cancer patients showed the potential for nuclear variants to interact with mitochondrial variants in a form of “cross-talk”. Mitochondrial mutations displayed a complicated interplay with nuclear mutational characteristics, and the two appear to work together to determine and drive tumour aggression.

    The team also found a link between mitochondrial mutations and biochemical relapse, and patients with both mutations in a specific non-coding region of the mitochondrial DNA and MYC copy number aberrations appear to have worse outcomes than those without. Further, older patients had more mtSNVs compared to those diagnosed at a younger age, a finding the researchers intend to investigate more.

    Proteins encoded in the mitochondrial genome are all part of the Oxidative phosphorylation pathwayand mutations in these genes can affect mitochondrial function, which has been shown to be essential for tumour development. Given this, the team believes it is important to identify any mutations in the mitochondrial genome, as well as to include its analysis in whole genome studies. The study suggests the addition of mtSNVs to prognostic biomarkers may be an effective way of improving prediction of patient outcome, supporting triage of patients with low-risk disease to surveillance protocols and with high-risk disease to adjuvant therapy regimens.

    Prostate cancer is the third leading cause of cancer-related death in Canadian men. Some types are aggressive and lethal, requiring aggressive treatment, while others are considered indolent and treatment may not be needed. These study findings can be used as a resource for future work in prostate cancer. It also underscores the importance of including the mitochondrial genome in future genomic analysis studies.

    Study: Mitochondrial mutations drive prostate cancer aggression

    Authors: Julia F Hopkins, Veronica Y Sabelnykova, Joachim Weischenfeldt, Ronald Simon, Jennifer A Aguiar, Rached Alkallas, Lawrence E Heisler, Junyan Zhang, John D Watson, Melvin LK Chua, Michael Fraser, Francesco Favero, Chris Lawerenz, Christoph Plass, Guido Sauter, John D McPherson, Theodorus van der Kwast, Jan Korbel, Thorsten Schlomm, Robert G Bristow & Paul C Boutros

    Funding: This project was supported in part by a Terry Fox Research Institute New Investigator Award to Paul C. Boutros.

  • 2017 Marathon of Hope Lecture Series

    by TFRI Editor | Feb 08, 2018
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    As part of its 10th anniversary celebration, TFRI presented a session titled The Marathon of Hope Lecture Series at the Canadian Cancer Research Conference(Vancouver) in November 2017 that featured four premier TFRI-funded researchers: John Dick (PM, Toronto), John Bell (OHRI, Ottawa), Stephen Lam (UBC, Vancouver) and Marco Marra, BC Cancer .
    We asked teach to speak on their vision of how their research may transform outcomes for cancer patients and bring us closer to achieving Terry's dream. The session was introduced by TFRI President Dr. Victor Ling and each speaker gave a 20-minute talk. We are pleased to present videos of all of the talks here, featuring slides presented. 
    We hope you enjoy these talks as much as those in attendance did!

    John Dick: Is stemness the biomarker and therapeutic target we have been missing?

    John Bell: Using viruses to stimulate the body's fight against cancer cells

    Stephen Lam; Lung cancer screening: Opportunity to improve health care delivery

    Marco Marra: Genomic approaches to cancer outcomes

  • 2017 TFRI Ontario Node Day Photos

    by TFRI Admin | Jan 19, 2018
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    The annual Terry Fox Research Institute’s Ontario Node Research Symposiumhosted by Drs. Marianne Koritzinsky, Trevor Shepherd, Sheila Singh and Robert Rottapel, took place Monday, Dec. 4, 2017 at the  MaRS Discovery Centre in Toronto. More than 200 people from across the province attended the event, entitled "Deconstructing and Reconstructing Tumour Complexity." 

    Check out photos from the event here



  • New study shows viruses and checkpoint inhibitors work together to cure resistant breast cancer in mice

    by TFRI Admin | Jan 03, 2018


    Drs. Marie-Claude Bourgeois-Daigneault and John Bell. 

    Immunotherapy, which helps the body’s immune system attack cancer, has revolutionized treatment for cancers such as melanoma and leukemia. However, many other kinds of cancer remain resistant. 

    A new study led by researchers at The Ottawa Hospital (TOH) and the University of Ottawa suggests that a combination of two immunotherapies (oncolytic viruses and checkpoint inhibitors) could be much more successful in treating breast cancer and possibly other cancers. The study, by members of  Dr. John Bell's lab in Ottawa, was funded by TFRI and other Canadian research partners and appears in Science Translational Medicine

    “It was absolutely amazing to see that we could cure cancer in most of our mice, even in models that are normally very resistant to immunotherapy,” said Dr. Marie-Claude Bourgeois-Daigneault, lead author of the study and a postdoctoral fellow. The work was conducted in mouse models.  “We believe that the same mechanisms are at work in human cancers, but further research is needed to test this kind of therapy in humans,” she said in a TOH press release dated Jan 3.

    In the current study, the researchers focused on “triple negative” breast cancer, which is the most aggressive and difficult-to-treat kind of breast cancer.The researchers studied three mouse models of triple-negative breast cancer, and found that all were resistant to a checkpoint inhibitor which is commonly used to treat other kinds of cancer. They also found that while an oncolytic virus called Maraba could replicate inside these cancers and help the mouse’s immune system recognize and attack the cancer, the virus alone had minimal impact on overall survival.

    The researchers then tested the virus and checkpoint inhibitor together in models that mimic the metastatic spread of breast cancer after surgery, which is very common in patients. They found that this combination cured 60 to 90 per cent of the mice, compared to zero for the checkpoint inhibitor alone and 20 to 30 per cent for the virus alone. In these models, the virus was given before the surgery and the checkpoint inhibitor was given after.

    “Our immune system is constantly trying to recognize and kill cancer cells, but the cancer cells are always trying to hide from it,” explained Dr. Bell, a senior scientist and project leader of TFRI's Program Project Grant on the Canadian Oncolytic Virus Consortium. “When you infect a cancer cell with a virus, it raises a big red flag, which helps the immune system recognize and attack the cancer. But in some kinds of cancer this still isn’t enough. We found that when you add a checkpoint inhibitor after the virus, this releases all the alarms and the immune system sends in the full army against the cancer.”

    A recently published clinical trial confirmed that oncolytic viruses and checkpoint inhibitors have potential for treating melanoma, but this is the first study to show the potential in breast cancer. It is also the first study to test viruses and checkpoint inhibitors in a surgery and metastasis model, which is particularly relevant for patients.

    Ongoing clinical trials are testing oncolytic viruses (including Maraba) in combination with checkpoint inhibitors in people with cancer. 

    The Maraba virus therapy was jointly pioneered by Dr. John Bell (The Ottawa Hospital, University of Ottawa), Dr. David Stojdl (Children’s Hospital of Eastern Ontario, University of Ottawa) and Dr. Brian Lichty (McMaster University), all members of the long-funded COVCo team.

    The research described here was published in Science Translational Medicine on January 3, 2018. The publication is titled “Neo-Adjuvant Oncolytic Virotherapy Before Surgery Sensitizes Triple-Negative Breast Cancer to Immune Checkpoint Therapy”.

     

  • The Potential of Precision Medicine: TFRI's 2017 ASM Photos Now Online

    by TFRI Admin | Dec 12, 2017
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    More than 200 cancer researchers attended TFRI's 8th Annual Scientific Meeting in Vancouver on Nov. 4. Under the theme "The Potential of Precision Medicine", the plenary sessions triggered some engaging discussion among attendees and the rapid fire poster talks introduced many trainees to the Terry Fox research family.

    Click here to see a selection of photos taken at the event.  

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