Research Grants 2009

Dr. Moulay Alaoui-Jamali, M.D. Ph.D.
Sir Mortimer B. Davis Jewish General Hospital, Montreal 
Targeting a novel heme oxygenase signaling pathway in prostate cancer and therapeutic applications
Basic Science - Therapeutics
When it is detected early and has not spread outside of the prostate gland (ie. has ‘metastasized’), prostate cancer is generally very treatable with drugs that interfere with the function of the male sex hormones (anti-androgen therapy). Unfortunately, treatment options are limited if the disease spreads throughout the body or becomes unresponsive to anti-androgen therapy, and these effects are major causes of death amongst prostate cancer patients. Dr. Alaoui-Jamali’s research group is investigating the biological processes that underlie the transition from early stage to late stage prostate cancer and the mechanisms that determine whether a particular tumour will respond to anti-androgen therapy. Dr. Alaoui-Jamali’s group has identified that a gene named heme oxygenase 1 (HO-1) is often turned on in prostate tumours that are unresponsive to anti-androgen therapy or that have metastasized. Furthermore, they have also identified a drug that blocks the function of HO-1 (an HO-1 ‘inhibitor’). In this grant, Dr. Alaoui-Jamali’s team will study how this HO-1 inhibitor affects prostate cancer cells, and will investigate whether the inhibitor can block the progression of prostate cancers in animal models of the disease. This research will help to identify whether these types of drugs could eventually be used to treat patients whose prostate cancer has spread or has stopped responding to anti-androgen therapies.

Dr. Maxime Bouchard, Ph.D.
McGill University - Montreal
Role of Gata3 in prostate cancer
Basic Science - Therapeutics
Many prostate cancers do not spread (metastasize) outside of the prostate, and thus will not threaten the life of the patient. Unfortunately, because oncologists currently do not have reliable tools to distinguish between those prostate cancers that will remain in the prostate and those that will spread and consequently threaten the life of the patient, many prostate cancers are treated too aggressively than is necessary. Since prostate cancer therapies can sometimes produce severe side-effects, it is very important to develop new tests that will help oncologists distinguish between prostate cancers that require aggressive treatments and those that do not. Dr. Bouchard’s research team has identified that a gene called GATA3 is often turned off in prostate cancers that have metastasized. In this grant, Dr. Bouchard will do further research to determine whether turning off the GATA3 gene is important for prostate cancer cells to gain the ability to metastasize outside of the prostate gland. The results of this research may therefore help in the development of a new tool to guide oncologists in the appropriate planning of treatment for prostate cancer patients, thus reducing the occurrence of side-effects in patients that do not require aggressive treatment.

Dr. William Chu, M.D. Ph.D.
Sunnybrook Health Science Centre –Toronto
Functional imaging of the prostate cancer metabolome with hyperpolarized Carbon-13 MRSI
Translational Science - Early Detection/Therapeutics
Prostate cancer cells often produce energy differently than normal cells (i.e. they have abnormal metabolism). In particular, the way that prostate cancer cells metabolize certain sugars and amino acids can be a hallmark of more aggressive disease that is likely to threaten the life of the patient. Dr. Chu’s research team will use a new form of Magnetic Resonance Imaging (MRI) to visualize the metabolic processes in prostate tumours. In particular, Dr. Chu’s group will investigate whether visualization of these processes can be used to monitor how prostate tumours are responding to radiation therapy. The team will initiate their studies on animal models of prostate cancer, and the results of these studies will help to transfer this technology to prostate cancer patients. Ultimately, these studies may help oncologists to identify early stage prostate cancer and to monitor how prostate cancer patients are responding to therapy.

Dr. Gregory Czarnota, M.D. FRCSC Ph.D.
Sunnybrook Health Science Centre –Toronto
Novel ultrasound antivascular prostate cancer therapy
Basic/Translational Science - Therapeutics
Ultrasound technology can be used to help oncologists identify prostate cancers. Dr. Czarnota’s group has recently identified that it may be possible to combine ultrasound with a technology called ‘micro-bubbles’, which under certain circumstances can be used to destroy the network of blood vessels that surround prostate tumours, and in turn kill the tumour by robbing it of its supply of blood and nutrients. This grant will allow Dr. Czarnota and his team to further investigate and refine this technique in animal models of prostate cancer. The use of both ultrasound and micro-bubbles are both approved for use in the clinic for other purposes, and thus if this research shows that Dr. Czarnota’s approach is effective in killing prostate tumours in mice, the technique could potentially be rapidly adapted for use in prostate cancer patients.

Dr. Yves Fradet, M.D. FRCSC
Centre Hospitalier Universitaire de Québec – Hôtel-Dieu de Québec. Québec
In vitro model of human primary prostate cells for the assessment of anti-inflammatory properties of chemopreventive agents
Basic/Translational Science - Prevention
Inflammation is a normal process that the body uses to defend against infections and to repair injuries. Occasionally, however, inflammation can become chronic, and this type of long-term inflammation has been linked to the development of prostate cancer. It is known that environmental factors, such as diet, can affect a person’s risk of developing prostate cancer, possibly by turning on or off genes involved in inflammation. In this grant, Dr. Fradet’s research team will grow cells taken from prostate biopsies and will treat these cells with various ‘micronutrients’, which are often found in foods that have been linked to a lower risk of developing prostate cancer. Dr. Fradet will examine whether specific micronutrients can affect the inflammation of prostate cancer cells, and whether micronutrients can decrease the risk of developing prostate cancer. Thus, Dr. Fradet’s research may lead to the development of new approaches to preventing prostate cancer using micronutrients.

Dr. Bertrand Jean-Claude M.D. Ph.D.
McGill University, Montreal
A multitargeted strategy towards the development of temodar and related molecules into novel chemotherapeutic agents against advanced prostate cancer
Basic Science - Therapeutics
Most chemotherapy drugs work by damaging the DNA molecule inside the cancer cells, which causes the cells to die. It has been shown that a gene called Epidermal Growth Factor Receptor (EGFR) is frequently turned on in advanced prostate cancer, and that tumours that have the EGFR gene turned on often do not die in response to chemotherapy. Drugs that block the function of the EGFR gene have been used successfully to help treat other cancers. Dr. Jean-Claude’s research team has developed a novel drug that blocks the function of the EGFR gene and also causes damage to the DNA. This grant will allow Dr. Jean-Claude’s team to further characterize the effects of this drug, and to investigate whether the drug will be effective in killing prostate cancer cells. It is hoped that this type of drug may one day be used by oncologists to help treat prostate cancer, and Dr. Jean-Claude’s work will be an important step toward this goal.

Dr. Andis Klegeris, M.D., Ph.D.
University OF British Columbia Okanagan, Kelowna
Use of mutasynthesis to create novel secondary actinomycete metabolites with potential antitumour activity
Basic Science - Therapeutics
Prostate cancer is generally very treatable when it is discovered early. However, when it is discovered after the disease has spread (metastasized) or has stopped responding to therapy, the disease becomes incurable. Moreover, some of the most effective treatments for prostate cancer can produce severe side effects that a man may have to deal with for the remainder of his life. Therefore, there is an urgent need to develop new effective treatments for prostate cancer, which also produce minimal side effects. Dr. Klegeris’ research team studies a molecule called azukamycin, which is produced by some types of bacteria. While azukamycin itself has only limited effects on killing prostate cancer cells, Dr. Klegeris believes that by modifying its chemical structure, azukamycin can be made to be more toxic to these cells. In this grant, Dr. Klegeris’ group will modify the genes that are responsible for producing azukamycin in bacteria, such that these bacterial will be forced to produce modified forms of the drug. The group will then purify these chemicals and test whether these drugs are effective at killing prostate cancer cells. Furthermore, Dr. Klegeris will study the precise mechanisms through which these drugs kill prostate cancer cells. It is Dr. Klegeris’ intention to create a ‘library’ of chemicals, all modified forms of azukamycin, which could be tested against a wide variety of cancer cells, and which could potentially be accessed by other researchers for testing on other cancer types.

Dr. Thomas Kislinger, Ph.D.
Ontario Cancer Institute. Toronto
Proteomic profiling of prostatic secretions: Biomarker discovery and validation
Clinical Science - Early Detection/Therapeutics
Prostate Specific Antigen (PSA) testing is used by oncologists to help in the diagnosis of prostate cancer, and to track whether treatments for the disease are successful. However, there are problems with the PSA test; PSA levels can sometimes be elevated in men who do not, in fact, have prostate cancer. For this reason, there is a need to develop better tests for the diagnosis of prostate cancer. Such a test would ideally involve detection of proteins in fluids that are secreted from the prostate gland, that are elevated in prostate cancer patients but not in individuals who do not have the disease; such proteins are termed ‘biomarkers’. In this grant, Dr. Kislinger’s team will use state-of-the-art detection technologies to identify proteins that are present in prostatic secretions from prostate cancer patients. They will follow up these studies by determining whether these identified proteins may serve as useful biomarkers for prostate cancer. The identification of such a novel biomarker would be an immensely useful tool for diagnosing and monitoring the progress of treatment for prostate cancer. 

Dr. Leigh Murphy, M.D. Ph.D.
Cancer Care Manitoba, Winnipeg
Differential role of the long and short form of estrogen receptor beta in human prostate cancer cells
Basic Science - Therapeutics
Sex hormones have important effects on the prostate gland. While a great deal of research has focused on the effects of the male sex hormones (e.g. testosterone), less is known about the influence of other sex hormones, such as estrogen, on the prostate gland and on the development of prostate cancer. Estrogen exerts its effects on the prostate by interacting with a protein called the estrogen receptor (ER), which comes in two varieties. It is thought that the first variety, called ER-alpha, causes the ‘good’ effects of estrogen on the prostate, while the second variety, called ER-beta, is involved in the development of prostate cancer. Dr. Murphy’s research team is studying the ER-beta protein to determine if and how it is implicated in prostate cancer. To accomplish this, Dr. Murphy is growing prostate cancer cells in the laboratory and examining the biology of these cells when ER-beta is turned on or off, and how ER-beta may interact with other proteins that are known to promote the development of prostate cancer. This research will help to determine whether ER-beta may be a good target for new therapies for prostate cancer.

Dr. Michael Pollak, M.D. FRCPC
McGill University, Montreal
PTEN loss and energy metabolism in prostate cancer
Basic Science - Therapeutics/Prevention
Like normal cells, cancer cells require a constant supply of energy to survive and grow. However, because they grow so quickly, cancer cells may require a disproportionate amount of energy to survive, and may produce energy (i.e. metabolize) in different ways than normal cells. Furthermore, it is clear that prostate cancer patients who also have obesity and high blood sugar levels have a poorer prognosis than other patient. For these reasons, many scientists now believe that changes in energy metabolism may promote tumour growth, and that cancer cells may be vulnerable to therapies that target their ability to produce energy. Dr. Pollak’s team will investigate the effects of growing prostate cancer cells in environments with high insulin and sugar levels, to examine whether this causes the cells to grow inappropriately. Dr Pollak’s group will also evaluate whether existing drugs that lower blood sugar levels, such as those used to treat some forms of diabetes, may be useful in the prevention and treatment of prostate cancer. Thus, this research may ultimately lead to novel therapies for prostate cancer, which interfere selectively with the cells’ ability to produce energy and to survive. 

Dr. Paul Rennie, M.D. Ph.D.
University of British Columbia, Vancouver
The Effects of Inhibition of L-Dopa Decarboxylase Activity by Carbidopa on Prostate Cancer Growth and Progression to Castration Resistance
Basic/Translational Science - Therapeutics
Prostate cancer is treated with therapies that target the production and/or function of the male sex hormones (anti-androgen therapy). Unfortunately, prostate cancer cells often gain the ability to resist these types of therapies, leading to a state known as androgen-independent disease, which is typically incurable. Scientists are attempting to discover precisely why prostate cancer cells resist these therapies, and to design new agents to circumvent this resistance. One possible reason for this resistance is that certain genes that mimic the effects of androgens may be turned in some prostate cancer cells, and this may override the anti-androgen therapies. Dr. Rennie’s group has shown that a gene called L-Dopa Decarboxylase, or DDC, may function in such a manner. Fortunately, there is already an approved drug, known as carbidopa, which targets DDC. It is not clear, however, whether this drug may sensitize prostate cancer cells to anti-androgen therapies. In this grant, Dr. Rennie’s research team will examine the effects of DDC and carbidopa on prostate cancer progression in animal models, and will examine if and how this drug may be a potential novel therapy for prostate cancer. 

Dr. Marianne Sadar, Ph.D.
BC Cancer Agency, Vancouver.
Proteomic investigation of a novel drug candidate for prostate cancer
Basic Science/Translational – Therapeutics
Patients with advanced prostate cancer are often treated with drugs that disrupt the production or function of androgens, which are the male sex hormones (known as anti-androgen therapy). Unfortunately, while most men respond to this type of treatment, most cancers will eventually become resistant to the treatment and will return in a form known as androgen-insensitive prostate cancer, which usually claims the life of the patient. Inside the cancer cell, androgen interacts with a protein known as the androgen receptor, and it is believed that alterations in the androgen receptor protein are responsible for androgen-insensitive prostate cancer.  Most of the currently available drugs that disrupt the function of androgens do so by blocking a certain part of the androgen receptor (known as the C-terminus). However, there is now a growing amount of evidence that suggests that a separate part of the androgen receptor (known as the N-terminus) could be targeted by new drugs, thus overcoming the problem of androgen-insensitive prostate cancer. Dr. Sadar’s group has identified several drugs that target the androgen receptor N-terminus, and in this grant, they plan to test the effects of these drugs on the function of the androgen receptor, and specifically on how the androgen receptor interacts with other proteins inside the cancer cell. By doing this, the group hopes to learn more about the biology of the androgen receptor, which could be informative for the development of new drugs to prevent and treat androgen-insensitive prostate cancer.

Dr. D. Robert Siemens, M.D. FRCSC
Queen’s University, Kingston
Defining the role of Cyclic GMP Phosphodiesterase (cGMP PDE) and Drug Resistance in Prostate Cancer
Basic Science - Therapeutics
Many cancers are treated effectively with chemotherapy drugs. Unfortunately, chemotherapy has not been very successful for advanced prostate cancer, and it is not clear exactly why this is the case. Many factors can influence whether a particular tumour will be killed by chemotherapy. This can include the biology of the cancer cells themselves. However, scientists now appreciate that the environment in which the tumour grows can play a significant role in influencing the ability of the cancer cells to grow, to spread (metastasize), and to become resistant to many therapies. Low oxygen levels (‘hypoxia’) in the cells and tissues surrounding the tumour has been linked to a more aggressive form of cancer that may be resistant to chemotherapy. In this grant, Dr. Siemens’ research group will investigate a small molecule called nitric oxide (NO), which is often found at low levels within cells that are growing under conditions of hypoxia. Dr. Siemens’ will examine whether blocking the function of the proteins that break down nitric oxide (called PDEs) may cause prostate cancer cells to be more effectively killed by chemotherapy drugs. There are already approved drugs that block the function of PDEs, and thus Dr. Siemens’ work may rapidly lead to novel treatments for prostate cancer.

Dr. Samy Suissa, M.D. Ph.D.
McGill University,  Ottawa
Metformin and the prevention of prostate cancer in patients with type 2 diabetes
Clinical Science - Prevention
Cancer cells require an abundant supply of energy to survive and to grow. There is some evidence that a drug called metformin, which is safe and is usually prescribed to patients with type 2 (adult onset) diabetes and is known to lower blood sugar levels, may have the ability to prevent the onset of some cancers. Unfortunately, little research has been done to evaluate whether metformin could be used as a preventative therapy against prostate cancer. In this grant, Dr. Suissa’s research team will conduct a study called a retrospective cohort, which looks at men who have taken metformin for their type 2 diabetes and examines whether these men had a lower risk of developing prostate cancer than men who did not take metformin for their diabetes. If this is the case, it is possible that metformin could one day be prescribed for certain men to prevent the development of prostate cancer. 

Dr. Joan Sweet, M.D. FRCPC
University Health Network, Toronto
Stromal Factors Promoting Prostate Cancer Progression
Basic/Translational Science - Therapeutics
Prostate cancer becomes potentially lethal when it spreads outside of the prostate gland (i.e. it metastasizes). Prostate cancer arises from the cells that line the surface of the gland (glandular epithelial cells). In order for these prostate cancer cells to spread, they must break through (or ‘invade’) the tissue that surrounds the gland, which is known as the stroma. The ability of prostate cancer cells to do this depends on the biology of the cancer cells themselves, but also upon the biology of the stroma. Furthermore, it is now thought that the stroma may also affect the initial development of prostate cancer, in addition to the spread of prostate cancer outside the gland. In this grant, Dr. Sweet’s research team will study how prostate stroma affects prostate cancer cells. In particular, Dr. Sweet will study if and how the prostate cancer cells can cause certain genes to be turned on or off in the stroma, and whether this may affect the ability of the prostate cancer cells to invade into the stroma. The team will also investigate whether the stroma can affect whether specific genes are turned on or off in prostate cancer cells. This research will clarify how prostate cancer cells and prostate stroma can interact with each other, and this knowledge could then be used to design new therapies targeted specifically at blocking these interactions.

Dr. Damu Tang, M.D. Ph.D.
McMaster University, Hamilton
Investigation of a novel metastatic factor in prostate cancer stem cells
Basic Science - Therapeutics/Prevention
Many scientists now believe that tumours may arise from a very small group of cells known as cancer stem cells (CSCs). It is thought that CSCs function as the ‘root’ of cancer; that is, they give rise to all of the cells in a particular tumour and chemotherapy and radiation therapy may be ineffective if they fail to kill off the CSC ‘roots’. To date, however, the search for prostate CSCs has been difficult and it is not yet clear what characteristics a prostate CSC has. Dr. Tang’s laboratory has recently identified a possible prostate CSC; these cells very potently produce tumours in mice. Moreover, Dr. Tang has identified a particular gene that is turned on only in prostate CSCs, and may help to promote the spread of prostate cancer outside of the prostate gland (i.e. metastasis). In this grant, Dr. Tang’s research group will examine cells taken from prostate cancer patients to see whether this gene is turned on in the prostate CSCs from these patients, and whether it is turned on specifically in those cells taken from patients with metastatic prostate cancer (i.e. cancer that has spread). Dr. Tang will also investigate whether turning this gene off in animal models of prostate cancer will prevent the cancers from metastasizing. If this is the case, Dr. Tang’s research may help in the development of new therapies aimed at specifically targeting prostate CSCs and at preventing prostate cancer from metastasizing.

Dr. Theos Tsakiridis, M.D. Ph.D.
McMaster, Hamilton
Pre-clinical evaluation of the role of AMP-activated Kinase (AMPK) in the response of prostate cancer (PrCa) to radiotherapy (RT). Evaluation of Metformin as an enhancer of RT response
Basic/Translational Science - Therapeutics
Radiation is one of the main ways that oncologists treat many patients with prostate cancer. However, many tumours can return even after high doses of radiation therapy. For this reason, radiation oncologists have need for additional therapies that could sensitize prostate cancers to radiation. Doing this, however, requires a better understanding of how prostate cancer cells respond to radiation. Dr. Tsakiridis’ research team has identified that turning on a gene called AMPK can cause more prostate cancer cells to be killed by radiation. Dr. Tsakiridis has shown that AMPK can be turned on by the drug metformin, which is already approved and in use for some patients with type 2 diabetes. In this grant, Dr. Tsakiridis’ research team will investigate whether metformin can be used to kill prostate cancer cells or to sensitize prostate cancer cells to radiation. To achieve this goal, the team will use animal models of prostate cancer and will also monitor the effects of metformin, radiation, or both on prostate tumours using modern technologies for visualizing tumours. Because metformin is already in use for type 2 diabetes, Dr. Tsakiridis’ research has the potential to be rapidly adapted for use in prostate cancer.

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