Research Grants 2004

Defining aggressive phenotype of prostate cancer using a multiplex panel of 12 gene model
Dr. Tarek Bismar MD, Lady Davis Research Centre, McGill University

Prostate cancer is for the most part a slow-growing disease and many men may not require aggressive therapy. In the management of early stage prostate cancer, one of the most challenging problems is, therefore, to identify those men who without treatment will eventually succumb to their disease. Genes control cell growth and may predict tumor behavior. Dr. Bismar’s team has identified 12 genes from men with prostate cancer, which may have a role in determining the aggressiveness of prostate tumors. They propose testing the levels of these genes in two groups of men with prostate cancer. The first group has been managed by watchful waiting and the second group has been treated by radical prostatectomy. As it is known which of these men developed problems secondary to their cancer and those who did not, Dr. Bismar hopes to correlate the level of these various genes with their eventual outcome. If this is possible, then ultimately measurement of gene levels within a tumor may differentiate those tumors which will behave aggressively and require treatment from those which are likely to behave in an indolent fashion and may safely be observed.

Therapeutic consequences of the implication of nuclear Fer in prostate cancer cell survival
Dr. Simone Chevalier PhD, Research Institute of the McGill University Health Centre

The treatment of advanced prostate cancer with hormonal therapy is initially successful in most cases. However, following a variable period of remission most men will relapse and again develop a progressive disease. This process is thought to be due to the presence of cells within the tumor, which are not dependent on male hormones for survival. These tumor cells have developed novel survival strategies, allowing them to survive and grow. Dr. Chevalier has discovered that prostate cancer cells, particularly hormone resistant cells, contain high levels of an enzyme Fer, which confers a survival advantage. Dr. Chevalier has also shown that manipulating the levels and distribution of this enzyme can restore sensitivity of these cells, to radiation. This new project will build on this work and hopefully allow for a novel therapeutic strategy in men with advanced prostate cancer.

A functional approach to identify tumor suppressor genes and markers of prostate cancer on human chromosome 18
Dr. Mario Chevrette PhD, The Research Institute of McGill University Health Centre

The exact processes by which prostate cancer changes from a slowly growing, relatively innocent process to a more rapidly progressive, aggressive disease are poorly understood. It is thought that alteration in levels of specific genes play a central role. This is because genes are the molecules which control and co-ordinate rates of cell growth. Dr. Chevrette has previously shown that certain groups of genes on chromosome 18 can inhibit the ability of human prostate cancer cells to metastasize or spread. He now hopes to identify and replicate these individual genes, and in so doing aims to determine the mechanisms by which this gene is inactivated in prostate cancer. Knowledge of these mechanisms may lead to the development of targeted strategies to prevent onset and delay progression of the disease.

Developing and assessing a technique for improved detection of prostate cancer using high magnetic field strength magnetic resonance spectroscopy (MRS)
Dr. Donal Downey MB, FRCPC, Robarts Research Institute, University of Western Ontario

A needle biopsy guided by ultrasound imaging is currently the standard method of establishing a prostate cancer diagnosis. The ability of ultrasound to accurately predict cancer in specific areas of the prostate is very limited. Therefore, ultrasound is used to allow representative sampling of the prostate rather than to target suspicious areas within the gland, which may be cancerous. As a consequence ultrasound guided biopsies may fail to detect cancers requiring patients to undergo a repeat biopsy. Prostate cancer can cause changes in the levels of certain chemicals within the prostate and MRS uses Magnetic Resonance Imaging (MRI) technology to detect these changes. Dr. Downey and his team have used last year’s grant to develop the novel technology required for this purpose. He will study a group of men who are about to undergo a radical prostatectomy to determine if the changes seen on MRS, conventional MRI imaging and 3-D ultrasound imaging, correlate with the findings noted when the prostates are removed and examined by a pathologist. It is hoped that development of such technology will ultimately improve the accuracy of prostate biopsies, result in fewer unnecessary biopsies and allow for earlier detection of the disease.

Mucins for prognosis and immunotherapy of prostate cancer
Dr. Yves Fradet MD, FRCSC, Universite Laval

Mucins are large proteins produced by most epithelial cells including prostate cells. Tumors continue to produce these mucins though they have usually been altered in some fashion. Immunotherapy (where the patients immune system is stimulated to kill tumor cells) is a promising treatment option for prostate cancer. The main obstacle to successful therapy is the difficulty in provoking an immune response and then sustaining it for sufficient time to kill malignant cells. As the immune system can recognize these subtle alterations, mucins are an attractive target for cancer vaccines. Dr. Fradet will analyze the production of these mucins in prostate cancer in order to design a vaccine, active against these particular tumors. Such work may help in the production of vaccines specifically designed to treat an individual patient’s tumor.

Targeting the EGR2-BNIP3 signaling in androgen-independent prostate cancer
Dr. Marek Los PhD, Institute of Cell Biology, University of Manitoba

Normal cells have a number of “control” pathways, which prevent rapid uncontrolled growth (tumor formation). Advanced tumors are thought to have lost many of these protective mechanisms and can therefore grow and spread rapidly. Dr. Los will attempt to reactivate one of these protective pathways and study its effect on prostate cancer growth. If this work shows promise in suppressing prostate cancer cell growth, Dr. Los will then test the specific products of this pathway to see which may have promise as the new chemotherapeutic agents in prostate cancer treatment.

Development of DC-based immunotherapy using erbB2 as a model antigen
Dr. Jeffrey Medin PhD, University Health Network

Immunotherapy (where the patients immune system is stimulated to kill tumor cells) is a promising treatment option for prostate cancer. The main obstacle to successful therapy is the difficulty in provoking an immune response and then sustaining it for sufficient time to kill malignant cells. Dendritic cells are specialized immune cells, which are capable of activating other immune cells to attack specific targets. Dr. Medin plans to modify dendritic cells so that they have an increased ability to recognize tumor cells and thereby increase their potential to mount an immune response to the tumors. If this strategy is successful it may help improve the success rates of such therapy in men.

The effects of androgen withdrawal and radiation therapy on the immune response to prostate cancer
Dr. Brad Nelson PhD, B.Sc, BC Cancer Agency

At the present time much effort is being devoted to the development of prostate cancer “vaccines”, which it is hoped, will boost a patient’s immune response to their tumor. Little is known however, of the effects of standard prostate cancer treatments, such as radiotherapy and hormonal treatment, on this response. Unlike surgery, radiotherapy and hormonal therapy may increase the activity of the immune system as the stimulus (tumor) remains in place during treatment. Dr. Nelson will collect blood, from men with prostate cancer, to determine if different forms of treatment alter the immune response. If differences are found he ultimately hopes to use this information in the development of a prostate cancer vaccine.

DNA repair SNP profiles and response to prostate cancer radiotherapy
Dr. Hilmi Ozcelik, B.Sc, M.Sc, PhD, Samuel Lunenfeld Research Institute, Mount Sinai Hospital

Some patients receiving radiotherapy for prostate cancer experience rectal and bladder side effects which limit the overall dose of radiation which can be given. This in turn reduces the overall effectiveness of radiotherapy. Currently, the ability to predict those patients who are likely to develop problems is very limited. Dr. Ozcelik will examine a group of genes, which are thought to play a key role in the recovery process following radiation treatment. By comparing the genetic “fingerprint” from men who experienced problems following radiotherapy to those who experienced no adverse effects, he hopes to identify men at particularly high risk of complications. This information would help clinicians advise patients which treatment is best for them and minimize side effects of future prostate cancer therapy.

Does O-glycosylation post-translational modification of beta-catenin regulate its oncogenic properties and prostate cancer
Dr. Sujata Persad PhD, McMaster University

Beta-catenin is a protein, which has two roles in the cell. It helps anchor cells to each other and it also limits the production of other proteins implicated in the development and progression of cancer. Though the amount of beta-catenin present in cancer cells is higher than in normal cells, for some reason it cannot enter the cell nucleus, which is essential if bata-catenin is to decrease production of these harmful proteins. It is now thought that catenin must bind to certain sugars (by a process known as O-glycosylation) to enable it to pass into the nucleus and exert it’s protective effect. Dr. Persad will investigate methods of modifying this process of O-glycosylation, and hopefully this work will allow the utilization of similar techniques in clinical practice in the future.

Relationship between hedgehog signaling and IGF physiology in prostate cancer
Dr. Michael Pollak MD, Lady Davis Institute for Medical Research, McGill University

Recently, a cell-signaling pathway called the hedgehog pathway has been implicated in the growth of prostate cancer. Hedgehog signaling is thought to influence cancers by altering levels of growth factors, which in turn increase tumor growth. Dr. Pollak will use an inhibitor of this pathway, cyclopamine, to determine the effect that blocking this pathway has on the growth of prostate cancer cells. Knowledge of this mechanism may lead to the development of novel strategies to treat and halt progression of prostate cancer.

Role and therapeutic implications of DNA methylation in prostate cancer
Dr. Shafaat Rabbani MD, Research Institute of the McGill University Health Centre

Cells that are damaged in any way are flagged for destruction and removal from the body by a process known as methylation. This allows the body to control and prevent growth of these abnormal cells. Tumors occur when cells proliferate in an uncontrolled manner and one of the processes thought to be responsible is abnormal methylation. Dr. Rabbani will attempt to restore the normal methylation pattern to prostate cancer cells. By so doing he hopes to be able to reverse the ability of cancer cells to grow and spread, particularly within bones. His ultimate goal is to design new therapeutic approaches to block the spread of prostate cancer to the bones – the main cause of prostate cancer related symptoms and complications.

Characterization of a novel PTEN negative regulator (p10nrgl1) mediated PTEN inactivation in prostate cancer
Dr. Damu Tang PhD, St. Joseph’s Hospital, McMaster University

Normal cells have a number of “control” pathways, which prevent rapid uncontrolled growth (tumor formation). PTEN is a protein produced by one of these pathways and it’s absence or lack of effect is thought to be a central event in the development of hormone resistant prostate cancer. Dr. Tang will study the mechanisms by which PTEN is inactivated. This knowledge may allow development of new strategies which prevent PTEN deactivation and thereby delay prostate cancer progression.

The role of androgen ablation in the conditioning of prostate cancer to photodynamic and other oxidative stress-based therapies
Dr. Brian Wilson, PhD, Ontario Cancer Institute, Princess Margaret Hospital

Photodynamic therapy involves the use of laser light to destroy tumors. The difficulty with this approach is limiting the toxicity (damage to healthy tissues) while maintaining therapeutic benefit. Photosensitisation involves administering an agent prior to therapy, which subsequently makes the tumor cells more susceptible to the effects of the laser. Dr. Wilson will study the effect of testosterone on these processes to see if decreasing testosterone levels can improve the therapeutic response. He hopes that improvements in this technology will allow prostate tumors to be treated in a minimally invasive fashion, with fewer side effects than current therapies.

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