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2014/2015 Research Grant Abstracts

The Canadian Breast Cancer Foundation – Prairies/NWT Region has invested into 11 research projects across the region as part of the 2014/2015 Research Grant Program. These projects are focused on developing targeted treatments to customize patient care, advancing risk prediction and reduction and improving methods of diagnosis in order to improve prognosis. 


University of Manitoba – Dr. James Davie DavieJames.png

TNF alpha gene signature in triple-negative breast cancer cells
 
Triple-negative breast cancer consists of different breast cancer subtypes, with poor prognosis, principally affecting women in their forties. There is currently no targeted therapy for the triple negative cancer group, which does not respond favorably to chemotherapies and radiotherapies. The tumor necrosis factor (TNF), a protein causing inflammation, is known to promote breast cancer development and metastasis. This proposes to clarify the TNF-induced gene programming, creating the TNF-response gene signature, for triple-negative breast cancer. Little is known about this gene programming, but it is believed the enzyme called MSK is involved.
 
This study, funded by the Canadian Breast Cancer Foundation – Prairies/NWT Region, will test the effects of several MSK inhibitors on the TNF-induced gene programming, particularly on the induced genes playing a role in tumorigenesis and metastasis.  This will aid in treatment decisions and determine the potential of MSK inhibitors in the treatment of triple-negative breast cancer.
 

University of Alberta – Dr. Mary Hitt HittMary.png

Multi-modality breast cancer therapy: combining oncolytic virotherapy with image-guided radiation therapy
 
Radiation therapy is a common treatment for breast cancer to target residual tumor cells left following surgery. Using advanced imaging techniques, the radiation beam can be directed precisely to the tumor site, preventing damage to surrounding normal tissues. However, microscopic extensions of tumor into the surrounding normal tissues may not be within the bounds of the radiation beam. In addition, some tumors do not respond to radiation. Previous studies from Dr. Hitt’s team have shown that a particular type of mutant virus is oncolytic; in other words, it is harmless to normal tissues, but can infect and destroy tumor cells.
 
This study, funded by the Canadian Breast Cancer Foundation – Prairies/NWT Region will, for the first time, examine the combination of image-guided radiation therapy with oncolytic vaccinia virus in mouse models for breast cancer. It is hoped that this research will generate the pre-clinical data needed to justify clinical trials for breast cancer - ultimately leading to an improved outcome for patients treated with radiation therapy.
 

University of Alberta - Dr. Kurian Joseph KurianJoseph.png

A cohort study assessing cardiac function with MRI in left sided breast cancer patients treated with deep inspiration breath-hold (DIBH) technique to improve cardiac sparing during adjuvant radiotherapy
 
Survivors of left-sided breast cancer are at increased risk of late cardiac toxicity. A combination of modern radiotherapy (RT) techniques and deep-inspirtation breath-hold is use to reduce the maximum dose to the heart. Furthermore, the risk of cardiac toxicity is increased when a patient receives raditation following adjuvant Anthracycline-based chemotherapy and Herceptin. A previous study showed that breast cancer patients receiving Herceptin, is associated with left ventricular cavity dilataion and reduced ejection fraction. The research team believes RT has detrimental effects on cardiac function due to remodeling of the cardiac tissue that receives radatition.
 
This study, funded by the Canadian breast Cancer Foundation – Prairies/NWT Region, will examine RT +/- chemotherapy mediated left ventricular remodeling (LVR) in women with left-sided breast cancer and quantify this. If RT induced LVR occurs, early interventions could be introduced to reverse the process and reduce late cardiac mortality.
 

University of Saskatchewan - Dr. Kiven Erique Lukong LukongKiven.png

Epigenetic regulation of the FRK tumor suppressor gene in triple negative breast cancers
 
Tumor suppressor genes usually encode proteins that regulate some aspect of cell growth. Loss of function or expression of these gene products is a hallmark of most cancers. FRK is such a candidate tumor suppressor and its expression is lost in a significant number of breast cancers. The research team has evidence suggesting this loss is controlled at the “epigenetic level”, a mechanism that turns off genes but does not alter the DNA sequence. Furthermore, this loss seems to be common in “Triple Negative” tumors, which are especially aggressive and hard to treat.
 
This study, funded by the Canadian Breast Cancer Foundation – Prairies/NWT Region, will have implications in both diagnosis and prognosis and will also help determine if drugs targeting the epigenome may be an option for this hard to treat form of breast cancer.
 

University of Manitoba - Dr. Leigh Murphy MurphyLeigh.png

Beyond the Estrogen Receptor: involvement of mechanistic target of rapamycin (mTOR) in estrogen signaling in normal and malignant human breast epithelial cells
 
Targeting estrogen receptor (ER) with tamoxifen is successful in treating and preventing breast cancer. Nevertheless, such therapies are limited due to resistance. Newer therapies, targeting ER, are also likely limited by development of resistance. Understanding the mechanisms of ER action holds promise for further increasing the approaches to treat ER+ breast cancer, the most frequent type of breast cancer. The more targets, the more likely the disease can be controlled. The development of more precise biomarkers of therapy response is valuable, so that the most appropriate therapies can be used quickly with minimal side-effects. The research team previously discovered that certain combinations of chemical changes called phosphorylation, on the surface of ER are more accurate biomarkers of prognosis than those currently used. The proteins called enzymes that cause the chemical changes on ER are being investigated as possible targets for new treatments.
 
This study, funded by the Canadian Breast Cancer Foundation – Prairies/NWT Region, will establish if the roles of mTORC1 in estrogen signaling are breast cancer specific. Such information could identify new targets leading to the development of new therapies for treating and preventing breast cancer.
 

University of Alberta - Dr. Lynne-Marie Postovit PostovitLynne-Marie.png

Role of Nodal in the hypoxic induction of breast cancer stem cell phenotypes
 
Approximately 30% of Canadian breast cancer patients will die of their disease, due to therapy resistance and metastasis. This research strives to improve this statistic by eliminating breast cancer stem cells (BCSCs) that drive recurrence and progression. Breast cancers contain areas where oxygen levels are lower than normal. Low oxygen levels cause an increase in BCSCs leading to metastasis and resistance to therapy. This research team has determined low oxygen levels cause breast cancer cells to turn on a protein called “Nodal”, that is normally only expressed in stem cells. This study will determine if Nodal promotes the formation of BCSCs and if blocking Nodal can prevent metastasis and disease recurrence. Nodal expression is largely restricted to stem cells, making it a selective target for breast cancer treatment.
 
This study, funded by the Canadian Breast Cancer Foundation – Prairies/NWT Region, will test whether Nodal can be targeted to eliminate breast cancer stem cells which contribute to treatment failure, recurrence, metastasis and ultimately death in breast cancer patients.
 

University of Manitoba - Dr. Afshin Raouf RaoufAfshin.png

Insights into deregulation of estrogen signaling network that occurs early in benign breast disease thought to be precursors to the development of invasive carcinoma
 
Early diagnosis of breast cancers greatly improves chances for successful treatment. Most breast cancers are estrogen-responsive and yet no reliable methods exist to diagnose these cancers at an early pre-cancerous stage. For this purpose, the mechanisms of estrogen action in healthy breast cells and then early changes in estrogen functions that are directly related to breast cancer development need to be identified. This research team has developed methods to study estrogen-regulated mechanisms in the healthy cells and cells in breast tissue at high risk of developing breast cancer.
 
The project, funded by the Canadian Breast Cancer Foundation – Prairies/NWT Region, will now study the nature of alteration to the estrogen-regulated mechanisms in healthy breast cells that lead up to breast cancer. The research team hypothesizes that some of these early changes could serve as diagnostic tools to detect breast cancers at an early premalignant stage.
 

University of Alberta - Dr. Wilson Roa

Radiation sensitive nanoparticles for targeted breast cancer therapy
 
Nanotechnology will dramatically change the future of Breast cancer therapy. Nanoparticles, due to their size, are able to preferentially concentrate within a tumor as a result of the irregular blood vessel formation which occurs within tumors as they grow.
Although chemotherapy agents such as doxorubicin are effective for breast cancer treatment, they can be toxic to the rest of the body. A method which would trigger the release of doxorubicin within a tumor, sparing the body from its toxic side-effects, would have tremendous patient benefit. In order to achieve this goal, this research team developed a polymer based nanoparticle capable of carrying doxorubicin within it. The polymer is stable under normal conditions, but can be triggered to break down when exposed to external beam radiation, thereby releasing doxorubicin. The exciting potential is that, as radiation can be given with extreme precision, the tumor will be more exclusively exposed to doxorubicin.
 
This study, funded by the Canadian Breast Cancer Foundation – Prairies/NWT Region, focuses on a radiation sensitive polymer coating (mPGA) which represents exciting future drug platforms capable of significantly reducing systemic toxicity. The gadolinium based nanoparticle further has the ability to function as an imaging tracer and radiation enhancer. These platforms could represent a significant advance in nanoparticle cancer therapy development.
 

University of Calgary - Dr. Carrie Shemanko ShemankoCarrie.png

Factors in the metastatic breast cancer microenvironment promoting bone resorption
 
Breast cancer spreads to the bone in 70% of patients with advanced disease. It can be debilitating and is associated with pain and increased risk of death. Treatment options are limited. Once breast cancer cells have traveled to the bone, they instruct the bone cells to specialize into bone-breaking-down cells. Understanding how the breast cancer cells instruct bone breakdown will identify signals that can be interrupted by therapy. This research team has identified a previously undiscovered mechanism that stimulates bone breakdown and are searching for therapeutic targets to reduce or stop bone loss. Better treatment will offer reduced disease burden and a better quality of life.
 
This study, funded by the Canadian Breast Cancer Foundation – Prairies/NWT Region, aims to understand the molecular mechanism by which breast cancer cells induce lytic bone lesions (bone resorption) upon metastasis and identify therapeutic targets.
 

University of Alberta - Dr. Alan Underhill UnderhillAlan.png

Epigenetic signatures of breast cancer progression
 
The genetic material we inherit from our parents is specially packaged to fit within the confines of a cell. This packaging (called ‘chromatin’) ensures genetic material is properly used and maintained. Cancer cells have come up with numerous ways to exploit the chromatin packaging material to their own end. They use some to promote uncontrolled growth, while getting rid of those that resist this process. This study addresses this last aspect and involves experiments to determine how this chromatin material gets rewritten when breast cells become cancerous. We have identified key defects in these processes in breast cancer cell lines and tumor samples and their cause is currently being explored.
 
This study, funded by the Canadian Breast Cancer Foundation – Prairies/NWT Region, will focus on whether the breakdown of a specific chromatin safeguard directly contributes to breast cancer progression, as well as its potential diagnostic and therapeutic use.
 

University of Manitoba - Dr. Wayne Xu XuWayne.png

Translational study of gene expression biomarker signature for breast cancer
 
Current biomarkers for breast cancer have low reproducibility for the diversity of patient types. This study focuses on a new idea that two opposing effects in cancer cells, named Yin and Yang, can predict breast cancer patient’s risk. This research team will identify Yin and Yang genes in both breast cancer and normal breast tissue samples to develop a Yin and Yang ratio biomarker.
 
This study, funded by the Canadian Breast Cancer Foundation – Prairies/NWT Region will help the clinical setting for breast cancer patients and enhance the panel of established breast cancer biomarkers. It also has potential in drug development through modulations to the Yin and Yang balance.


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