Research Grants 2007

Funded in June 2007, and executed in 2007-08

Molecular mechanisms for cavernous nerve neuroprotection and regeneration following injury due to prostate cancer treatment in diabetic men
Dr. Anthony J Bella, MD, University of Ottawa

Surgery is a curative treatment for early prostate cancer; however, erectile dysfunction (ED) is a major complication following surgery due to unavoidable damage to the nerves responsible for erection (the cavernous nerves). Data suggests that up to 70% of men are not able to attain or maintain an erection sufficient for sexual intercourse 12-18 months after surgery. This serious side-effect significantly impacts the care of men with prostate cancer. Patient and partner quality of life are significantly impacted, and patients are at increased risk of depression, lowered self-esteem, and relationship problems. In fact, some men delay treatment for their prostate cancer in order to avoid ED. Diabetic men are particularly at risk of ED after surgery, as diabetes alters the healing process. Dr Bella and his colleagues have previously identified a growth factor (a naturally occurring protein that can stimulate growth), which helps preserve erectile function in rats subjected to cavernous nerve damage. In this current study, they will determine how this growth factor (as well as others) protects the cavernous nerve using diabetic rats. Although this study focuses on diabetic men, the approach and possible treatment options would apply to both diabetic and non-diabetic men. Additionally, it is thought that nerve protection or regeneration strategies could also be used in treating radiation-induced nerve injury as seen with external beam and brachytherapy treatment for prostate cancer.

Impact of Antioxidants on MRI Markers of Cell Proliferation and Hypoxia Among Men on Active Surveillance With Early Stage Prostate Cancer
Dr. Neil Fleshner, MD, FRCSC, MPH, University Health Network

There is evidence that antioxidant vitamins (specifically vitamin E, Selenium and Lycopene) may prevent or slow the growth of prostate cancer. In this research study, Dr Fleshner and colleagues are looking at the effect of antioxidants on prostate tumour growth using Magnetic Resonance Imaging (MRI). They will be giving men with visible tumours on MRI who are not receiving any active treatment but are being followed closely for their low risk prostate cancer (called ‘active surveillance’ or ‘watchful waiting’), a once daily combination capsule containing the antioxidants vitamin E, selenium and lycopene for one year, OR a daily capsule containing no active ingredients. The men will have MRIs repeated after having taken the antioxidants for 1 year, and again at 2 years (after half of the men are no longer taking the antioxidants). If significant changes in the prostate tumour are noted on MRI, Dr Flesher and his research team will consider conducting a larger clinical trial to determine whether antioxidants could represent an alternate option for men with low risk disease who wish to have treatment with minimal side effects. This study holds great promise to potentially alter the burden of prostate cancer in Canada and throughout the world.

Does lifetime sun exposure, insulin resistance, and vitamin D predict prostate cancer aggressiveness?
Mr. Richard Gallagher, MA, Fellow, BC Cancer Agency

Prostate cancer is the most common life-threatening cancer in Canadian men, but unfortunately we know very little about the causes of the disease. One possible, but hotly debated risk factor for developing prostate cancer is obesity. The investigators headed by Mr. Gallagher, are currently conducting a large study to see if factors that are associated with obesity (such as insulin resistance) contribute to their chances of developing prostate cancer. They are also looking at whether high levels of sun exposure (which increases vitamin D levels in blood) protects against prostate cancer, as has been proposed by other studies. The aim of the current research is to determine if these factors can also predict whether a man’s prostate cancer will be aggressive or not. Since most of these factors are modifiable through diet, exercise, and vitamin supplementation, this study could lead to new ways of reducing the risk of progression and death in men already diagnosed with the disease.

Oncolytic HSV-1 with a 3'UTR regulatory element for prostate cancer specific virotherapy
Dr. William Jia, Ph. D, University of British Columbia

Viruses are very small particles that infect human cells and use them in order to reproduce, and as a result lead to the death of the cell. One example of a virus is the one that causes the common cold. Virotherapy is a treatment approach that uses viruses to infect specific cells (cancer cells, for example), kill them, and then spread to other cells in the same area to destroy them also. While this cell destruction can be very efficient, it is important to ensure the virus only infects tumour cells and does not spread to the normal cells in the vicinity, as this would cause unwanted side effects. Dr Jia and his research team have created a virus that infects and kills prostate cells. They are currently working on trying to improve the virus’ ability to specifically infect prostate tumour cells while sparing normal prostate cells. This should lead to the development of novel treatment for advanced cancers.

Small Molecule Inhibitors of Prostate Cancer Bone Metastases 
Dr. Jan Jongstra, Ph. D., University Health Network

Spread of prostate cancer to bone (bone metastasis) is an unfortunate, but very common occurrence in late stage prostate cancer. Bone metastases are a major source of symptoms such as pain, fractures, spinal cord damage and destruction of the blood forming cells in the bone marrow leading to anemia and infection. Ultimately, bone metastases can also lead to death. Current chemotherapy treatment for late stage prostate cancer patients is aimed at inhibiting the growth of prostate cancer cells and is not specifically aimed at tumour cells that have spread to bone, which are more difficult to treat. The objective of Dr Jongstra’s research program is to develop new chemotherapy agents for treatment of late stage prostate cancer patients. They have developed a new agent that is active against prostate cancer cell lines that are grown in a controlled environment (essentially a ‘test-tube’) in the lab, but with little activity against normal cells. The agent also appears to be very active against prostate cancer that has spread to the bone. Dr Jongstra plans on testing its activity in mice with prostate cancer bone metastases. These experiments will lead to further development of this chemotherapeutic agent for treatment of late stage prostate cancer patients with the potential of significantly improving the quality of life or even be curative.

Electro catalytic Detection of Prostate Cancer Biomarkers 
Dr. Shana Kelley, Ph. D., University of Toronto

While curative therapies are available for prostate cancer, they are most effective when it is caught at a very early stage. The most common mode of testing, involving the measurement of prostate-specific antigen (PSA) levels in the blood, unfortunately is unable to accurately diagnose prostate cancer early. Dr Kelley and colleagues are attempting to develop new technologies for detecting prostate cancer. They plan on using electrical signals to monitor changes at the molecular level (specifically in genetic material called DNA) that are known to be signs of prostate cancer. The results will allow diagnostic devices to be made that are inexpensive and highly practical for use in the clinic. By developing a diagnostic test that is more accurate and sensitive than those currently available, the death rate from prostate cancer may be significantly reduced.

Identification of Novel Tumour Suppressor Genes in Prostate Cancer
Dr. Jacques Lapointe, Ph. D. MD, McGill University

Prostate cancer displays a broad range of clinical behavior from relatively slow growing to aggressive disease. How to predict the outcome and what changes at the level of the cell underlie the differences in the clinical course of the disease are two important questions. Through analyzing the differences between cancer cells, Dr Lapointe’s team has identified three clinically relevant subgroups of prostate tumours. The objective of this research is to study one of the alterations in the genetic material (DNA) found in a subgroup of tumours that has not characterized yet. This research will improve our understanding of prostate cancer development and may identify new diagnostic and prognostic markers as well as targets for cancer therapy.

Enhancement of FasL-Mediated Killing of Primary Prostate Cancer Cells
Dr. Jeffrey Medin, Ph. D., Ontario Cancer Institute, University Health Network

The immune system contains cells that have the potential to fight cancer, but under normal conditions they are not efficient killers of tumour cells. The field of ‘immunotherapy’ looks to boost the immune system’s ability to recognize and kill tumour cells. For example, recent clinical trials have been using a group of immune cells called ‘T cells’, which have been grown outside the body to large numbers and injected back into the patient. Encouraging responses have been seen when this approach is used against prostate cancer, but no increase in life expectancy has been shown. Dr Medin and his team are working on increasing the ability of these T cells to kill prostate cancer cells, so that someday it can be a useful treatment option. They are also trying to identify proteins called ‘inhibitors’ that stop the T cells from killing prostate cancer. Identification of these ‘inhibitors’ may lead to development of methods that boost our body’s defense against developing prostate cancer.

Involvement of I-kappaB kinase-epsilon (IKKe) in dysregulation of cytokine expression and prostate cancer progression
Dr. Anne- Marie Mes-Masson, Ph. D., CHUM – University of Montreal

Hormone treatment is the first line of treatment for advanced prostate cancer but, eventually, prostate cancer stops responding to this therapy and progresses to a disease stage that is described as ‘hormone-resistant’. The progression of prostate cancer to the hormone-resistant state is thought to be a multi-step process involving factors such as cytokines. Cytokines are a diverse group of molecules that are naturally produced in our body which regulate inflammation and our immune system. There is evidence that men with hormone-resistant disease have significantly elevated levels of cytokines that may encourage the growth of prostate cancer.

Dr Mes-Masson and her team are looking at cytokine production in prostate cancer. They recently discovered a cytokine that is highly active in hormone-resistant prostate cancer cells. They plan on using this cytokine as a treatment for prostate cancer growth in mice. This work will provide a model for similar treatment in men with prostate cancer. A better understanding of cytokine involvement in prostate cancer could open new research avenues to better understand the development of hormone-resistance which could eventually lead to the development of new therapies.

Expression, regulation and role of the anti-apoptotic Mcl-1 protein in controlling prostate cancer cell survival
Dr. Jorg Michels, MD, MRCP (UK), Ph. D., Fellow, BC Cancer Agency and Deeley Research Centre

Although early stage prostate cancer can be cured with radiotherapy or surgery, treatment options are of limited effectiveness once patients are diagnosed with advanced or recurrent prostate cancer. Current thinking is that the discovery of new therapies will be derived from increasing knowledge about the key biological processes that cause the progression of prostate cancer. Dr Michels’ research team are interested in a family of proteins that naturally occur in our bodies that are involved in how cancer cells die. One such protein, called Mcl-1, is important in that it has been shown to be produced by other cancer types, and gives the cell a survival advantage by inhibiting those processes in the cell which would normally lead to it’s death. The purpose of Dr Michels’ team’s research is to perform in depth investigations to determine the role of Mcl-1 in prostate cancer. Specifically, they will attempt to prevent the action of Mcl-1 in order to negate the survival advantage it gives prostate cancer cells when treated with chemotherapy. The results bear great potential to enhance the biological understanding of prostate cancer and develop novel, more effective treatment strategies for patients with prostate cancer.

Sulfatase Steriod Inhibitors – a new therapeutic tool for treating Prostate Cancer
Dr. Donald Poirier, Ph. D. Post-Doc, University of Laval

Androgens, such as testosterone, stimulate prostate cancer cells to grow as well as become more aggressive. Steroid sulfatase (STS) is an enzyme that is involved in the production and regulation of androgens. The inhibition of this enzyme to control it’s stimulating effects on cancer tumours is therefore a valid approach in the treatment of prostate cancer. Dr Poirer’s research group has been developing inhibitors of STS for several years. Recently they have identified a promising STS inhibitor that they will be further analyzing. They plan on determining the inhibitor’s ability to block prostate cancer growth caused by androgens by looking at human prostate cancer tumours that are injected into mice. This work will provide a model for similar treatment in men with prostate cancer, and is an essential step in evaluating the potential of the STS inhibitors as a new therapeutic tool for the treatment of prostate cancer.

SiRNA Knockdown of Androgen Receptors to Treat Androgen-Independent Prostate Cancer
Dr. Paul Rennie, Ph. D., University of British Columbia

Using medications that block the production or action of the male sex hormones called androgens (‘hormone-treatment’), is the first-line therapy for recurrent and metastatic prostate cancer. Unfortunately though, while initially very effective, in most men the cancer ultimately progresses to a lethal ‘hormone-resistant’ state. While the mechanisms responsible for the development of hormone-resistant prostate cancer are largely unknown, high levels of the protein that normally transfers the hormone signal, the androgen receptor (AR), are a common feature. Recent work done by Dr. Rennie and his collaborators reported that they could decrease the production (‘knockdown’) of the AR protein in human prostate cancers using a new drug. In the present study, they will test different systems for delivery of this drug, in order to determine which is most efficient. The plan on testing a new approach that will allow them to specifically and efficiently target advanced prostate cancer cells. These experiments will reveal if this newer prostate-specific targeted delivery system is superior to a more general approach. Since progression to the androgen-independent state is the end stage of prostate cancer, Dr Rennie’s AR ‘knockdown’ strategy could have a major impact on the survival of men with advanced, androgen-independent prostate cancer.

Targeting the death receptor pathway of caspase activation for the treatment of prostate cancer
Dr. Aaron Schimmer, Ph. D, MD, Post-Doc Fellow, Princess Margaret Hospital

Normal cells in our body, including prostate cells, have a limited life span. After a specific length of time, or after having experience some ‘fatal’ damage (from radiation or chemotherapy for example), the cells undergo a process (also known as a ‘pathway’) that leads to their death. Cancer cells have defects in this ‘death pathway’ and therefore grow uncontrollably despite being exposed to the damage that cancer treatment such as chemotherapy inflicts. This in part explains why even the best chemotherapy agents that we use for advanced prostate cancer only increase life expectancy by a number of months. Dr Schimmer and his colleagues are studying a new prostate cancer treatment agent that appears to restart the ‘death pathway’ in cancer cells exposed to chemotherapy. They plan on determining how this new agent works, in order to develop newer, more effective therapies. Development of such treatments could be used to increase the effectiveness of standard chemotherapy and lead to longer life expectancies in men with advanced prostate cancer.

Role of nitric oxide signaling in hypoxia-induced resistance of prostate cancer cells to the natural cytotoxic activity of peripheral blood lymphocytes
Dr. D. Robert Siemens, MD, FRCSC, Queen’s University

The environment that cancer cells live in plays a significant role in their ability to grow and invade throughout the rest of the body. There are many factors that contribute to a more invasive cancer, some of which allow tumour cells to avoid detection and killing by our immune system. One factor that has been shown to cause a more aggressive, invasive cancer is low oxygen levels. Dr Siemens research team plan to investigate the role of low oxygen levels and how it affects the ability of prostate cancer cells to escape killing by our immune system. Furthermore, they will also look at particular changes in cancer cells growing in a low oxygen environment that may enable this resistance. The overall aim of their research is to identify factors that can be given to men with prostate cancer that will help the immune system kill cancer cells.

The interplay between BMI1 and PTEN in prostate cancer tumourigenesis 
Dr. Damu Tang, Ph. D., McMaster University

Prostate cancer is a disease that results from the uncontrolled growth of initially normal prostate cells. Normal prostate cells have a limited lifespan. A process called ‘senescence’ (which is the scientific word for ‘aging’) prevents prostate cells from uncontrolled growth. Bypassing senescence is therefore required for cells to develop into cancer. Dr. Tang and his colleagues have been studying the protein named BMI1, which is known to cause uncontrolled growth of cells in cancer of the breast and other tissues. They have recently found that BMI1 may also be involved in the initiation or progression of prostate cancer, and that another protein called PTEN may be important in regulating BMI1’s action. They now plan to investigate how BMI1 may lead to prostate cancer in some patients. This research will deepen our understanding how normal prostate cells become cancerous, and may facilitate the development of novel prostate cancer therapies targeting BMI1.

Phase 2 study of second-line high-dose Ara-C (cytarabine) in metastatic hormone refractory prostate cancer
Dr. Ian Tannock, Ph. D, MD, University Health Network

Chemotherapy is used in the treatment of prostate cancer that no longer responds to androgen deprivation, or as it is commonly known, ‘hormone-treatment’, however the increase in life expectancy men get from even the most effective chemotherapy is only a number of months. It has recently been discovered that in a large proportion of prostate tumours there is an abnormality in the genetic material (called DNA) that causes the production of an abnormal growth signal. Making drugs that block this growth signal is difficult, however a drug that currently exists, known as cytarabine, may be effective but has never been tested in prostate cancer. Dr Tannocks’ research team carried out experiments on prostate cancer cells grown in a laboratory and found that they were sensitive to cytarabine. To investigate the use of this drug further, they plan to give it to men who have failed the most effective chemotherapy that we have for prostate cancer in a type of clinical trial known as a "phase 2" trial. The aim of this trial is to determine any unanticipated side-effects of this drug and to determine how effective it is in killing prostate cancer. This trial will therefore provide the opportunity to intergrate new knowledge from both clinical and scientific practice in order to improve treatment of advanced prostate cancer.

Androgen Modulation of Protease Activity in a pten-/- Prostate Cancer Model
Dr. Geoffrey Wood, Ph. DVSC, Samuel Lunenfeld Research Institute

Progression towards advanced prostate cancer is characterized by altered production of proteins in the prostate cell. Some of these proteins, called enzymes, are needed for the prostate cancer cell to be able to invade the tissues outside of the prostate itself, as well as gain access to the bloodstream. Normal prostate cells generally have other proteins, called ‘inhibitors’, which block the action of the enzymes that allow invasion. Dr Wood’s research team has been studying one of these inhibitor proteins (named TIMP3), which although is produced in normal prostate cells, is absent in advanced prostate cancer cells, which may explain why they are able to become more invasive. Dr Wood has shown in previous experiments that this inhibitor protein can suppress the growth of breast cancer cells in mice. They now plan on determining the role of TIMP3 in prostate cancer. If it proves to be important in the development of advanced prostate cancer, it may provide a target for a therapeutic agent in the future.

Prevalence and age distribution of Prostate Carcinoma and its precursor lesions in African, Asian and Caucasian men in autopsy specimens: a prospective comparative international study with central pat 

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