Research Grants 2003

Funded in December 2003, and executed in 2004 and 2005

Altered intracellular trafficking of DNA repair proteins in prostate cancer
Dr. Robert G. Bristow MD, PhD, Princess Margaret Hospital-University Health Network

All normal living cells have the capability of repairing damage to their genes should it occur during a cell's lifespan. This ability is often lost in cancer cells, allowing for the accumulation of genetic damage, which can lead to disorganized growth and disease progression. Dr. Bristow will study a specific protein involved in gene repair called Rad51 and look at its role in the initiation of prostate cancer. He will try to discover the means by which this protein is unable to do its job and the implications it may have on the administration of various therapies. More specifically, he will try to uncover if a defect in this gene repair pathway gives cancer cells the ability to resist standard drug therapies and radiation treatment. Uncovering this may lead to better risk assessment of men with prostate cancer and development of strategies to work around this defect and allow for better drug and radiation therapy.

Inhibiting telomerase in prostate cancer cells
Dr. Mario Chevrette PhD, McGill University

Telomerase is an enzyme that is thought to give prostate cancer cells immortality. Dr. Chevrette's preliminary work suggests that normal cells lack this enzyme because its expression is inhibited by another 'repressor' gene. He proposes to identify this 'repressor' gene and find out why it is absent in prostate cancer cells. This knowledge could provide a powerful weapon against prostate cancer cells by leading to therapies that restore their mortality. The effect on non-cancer cells would be negligible as they normally express this 'repressor' gene.

Three-dimensional ultrasound-guided prostate biopsy: a new system
Professor Joseph L. Chin MD, University of Western Ontario

A needle biopsy guided by two-dimensional ultrasound imaging is currently the standard method of establishing the diagnosis of prostate cancer. Although this method works well in determining whether or not cancer is present, it is unable to precisely localize where the cancer is within the prostate. Dr. Chin will develop and test a three-dimensional ultrasound system to biopsy prostates in order to precisely map the location of the cancer. Such localization will enable doctors to be more precise when a second biopsy is required for certain pre-cancerous states discovered on an initial biopsy. This information will prove invaluable to doctors making therapeutic decisions, leading to improved patient care and outcomes.

Developing and assessing a technique for improved detection of prostate cancer using high magnetic field strength magnetic resonance spectroscopy (MRS)
Radiologist Donal B. Downey MD, BCh, BAO, MSc, FRCPC, RobartsResearch Institute, The University of Western Ontario

A needle biopsy guided by two-dimensional ultrasound imaging is currently the standard method of establishing the diagnosis of prostate cancer. Although this method works reasonably well, it often fails to detect a cancer that is present, requiring patients to undergo repeated biopsies. Dr. Downey will use Magnetic Resonance Imaging (MRI) technology known as Magnetic Resonance Spectroscopy (MRS) in association with a three-dimensional ultrasound system to find areas within the prostate that are more likely to be cancerous. This would provide better guidance for the biopsy needle and increased biopsy yield. Ultimately this will result in fewer unnecessary biopsies and the ability to diagnose prostate cancer earlier, when it is more likely to be curable.

Feasibility study of bone-related proteins by immunohistochemistry using archival specimens of prostate adenocarcinoma
Dr. Helga Duivenvoorden PhD, Northwestern Ontario Regional Cancer Centre

Advanced prostate cancer is known to have a tendency to spread to the bones, which results in significant pain and disability. Dr. Duivenvoorden will study two proteins (RANKL and OPG) that are involved in the regulation of bone growth. She will try to determine their role in prostate cancer's ability to spread to and destroy bones. Knowledge of this mechanism may lead to the development of targeted strategies to stop the progression of prostate cancer.

Enhancing the chemosensitivity of p53 null prostate cancer cells by targeting checkpoint genes using RNA interference
Dr. Gerardo Ferbeyre MD, PhD, Université de Montréal

One of the main difficulties in finding therapies to treat prostate cancer is our inability to selectively target cancer cells while leaving normal cells unaffected. Dr. Ferbeyre will use a novel technique called RNA interference (RNAi) to take advantage of known gene mutations present in prostate cancers in order to increase their sensitivity to known chemotherapeutic agents without harming normal cells. His preliminary studies have demonstrated the feasibility of this approach and this new project will build on this work. The potential payoff will be in the form of treatments that kill cancer cells without causing debilitating side effects in the patient.

Noninvasive longitudinal assessment of antioxidant effect on prostate cancer progression in a transgenic animal model*
F. Stuart Foster PhD, Dept. of Medical Biophysics, University of Toronto, Sunnybrook Health Sciences Centre

Antioxidants are naturally occurring compounds such as Vitamin E, Selenium and Lycopene. Recent studies suggest that they may play an important role in preventing prostate cancer. Dr. Foster will study their effects on cancers in a mouse model by using a novel non-invasive three-dimensional ultrasound technique. The ability to follow tumors, in live animals, over time may provide important insights into how antioxidants affect prostate cancer over time. Ultimately, this may lead to a better understanding of which antioxidants are most effective and at what time is their introduction optimal. Furthermore, if successful, the same technology may be used to monitor the effects of other therapies on prostate cancer, accelerating our chances of finding a cure.

* Co-funded with Canadian Prostate Cancer Research Initiative

TEPC, a novel model for human prostate cancer
Dr. Rama Khokha PhD, Ontario Cancer Institute

Medical progress in the fight against cancer often requires an animal model that allows researchers the necessary flexibility when studying some of the molecular processes that are involved in the formation of cancer cells. Dr Khokha has developed a new mouse model that appears to mimic human prostate cancer more closely than previous models. Further characterization of this model is still necessary. This study may unlock some of the mechanisms by which prostate cancer spreads to lymph nodes and to bones. This knowledge may lead to novel therapies to halt its spread.

Immunotherapeutic augmentation of reovirus oncolysis in an orthotopic model of murine prostate cancer*
Dr. Don G. Morris MD, PhD, Tom Baker Cancer Centre / University of Calgary

Recent research into prostate cancer treatment has used viruses to attack cancer cells. Success with these approaches has been limited because the immune system often wipes out the virus before it can accomplish its task. Preliminary studies have demonstrated the naturally occurring reovirus, a commonly found environmental virus, to be selective against cancer cells while having little effect on normal cells. Dr. Morris will attempt to use the reovirus not only to attack cancer cells, but to also recruit the immune system into attacking them. This two-pronged approach may also work like an anti-tumour vaccine, preventing future recurrence of the prostate cancer. Dr. Morris will conduct the experiments in a mouse (murine) model of prostate cancer.

* Co-funded with Canadian Prostate Cancer Research Initiative

Insulin-Like Growth Factor-1 and high grade Prostatic Intraepithelial Neoplasia 
Dr. Robert K. Nam MD, FRCSC, Sunnybrook & Women's College Health Sciences Centre, University of Toronto

It is believed that a lesion known as high-grade intraepithelial neoplasia (also referred to as HGPIN) is a precursor of prostate cancer. Dr. Nam will study a protein that is found in the blood called insulin-like growth factor -1 (IGF-1) to see if it is increased in men who have HGPIN. This information will give us insight into whether IGF-1 is associated with one of the steps that occur with the transformation of normal tissue into malignant tissue. This knowledge can aid in the development of novel detection and prevention strategies.

The effects of androgen withdrawal and radiation therapy on the immune response to cancer
Dr. Brad H. Nelson, B.Sc. Ph.D, Senior Scientist, Director Deeley Research Centre, BC Cancer Agency, Vancouver

Treatment of prostate cancer has been significantly improved by the combined use of hormone therapy and radiation therapy; however, why this particular combination of therapies works is not well understood. A possible reason may be the activation of the immune system against the tumor by the combined treatments. Dr. Nelson will study the role of the immune system with the combined use of hormone and radiation therapy in a mouse model of prostate cancer and later, in patients. If the role of the immune system in this context is confirmed, it may be possible in the future to further improve outcomes from combined hormone therapy and radiation therapy by giving patients vaccines or other drugs that further enhance the anti-tumor activity of the immune system.

Post-translational modifications of the androgen receptor and their role in progression to androgen-independent prostate cancer*
Dr. Paul S. Rennie PhD, University of British Columbia/Vancouver General Hospital

Prostate cancer is known to be an androgen-sensitive tumour. This means that androgens, such as the hormone testosterone, facilitate its growth and consequently their removal can cause cancer regression. However, with time, prostate cancer becomes androgen independent, meaning its growth no longer depends on the presence or absence of androgens. How this happens is unknown. Dr. Rennie proposes that subtle modifications to the androgen receptor within a prostate cancer cell may be responsible for this process. He will study these modifications employing sophisticated protein purification and mass-spectrometry techniques. Once the mechanism of androgen independence is uncovered, it can lead to therapies that prevent or delay it, thus prolonging the lives of patients with prostate cancer.

*Co-funded with Canadian Prostate Cancer Research Initiative

Magnetic Resonance Spectroscopic Imaging for improved treatment planning of prostate cancer
Dr. Lawrence N. Ryner PhD, University of Manitoba

Current methods to diagnose prostate cancer are able to determine whether or not cancer is present, but are unable to precisely localize where the cancer is within the prostate. Dr. Ryner will improve on existing Magnetic Resonance Spectroscopy Imaging (MRSI) technology in order to map the location of the cancer within the prostate. He will then use this in conjunction with radiation therapy in order to deliver higher doses of radiation to the cancerous parts of the prostate. If successful, this strategy will increase the efficacy of the treatment while avoiding additional collateral damage to surrounding structures.

Role of ErbB receptors in the constitutive activation of NF-kB in CaP 
Dr. Fred Saad, M.D., F.R.C.S. Associate Professor Surgery/Urology, University of Montreal 

It is well recognized that many men die with prostate cancer rather than because of it. The reason for this is that in some cases the cancer is slow growing while in others it can be more aggressive. Currently we do not have an accurate way of differentiating the two. Dr. Fred Saad will study two proteins called ErbB and NF- k B thought to be involved in the progression of prostate cancer to determine if their interaction can be used to predict which cancers are destined to progress and which are not. This knowledge may lead to a better understanding of which cancers require aggressive treatment and which do not.

Telomere erosion as an early biomarker of prostate cancer
Dr Jeremy A. Squire BSc, MSc, PhD, University Health Network

Telomeres can be thought of as caps on the ends of chromosomes, which stabilize their decline and possibly give cells a fixed lifespan. Dr. Squire will study the role of telomeres in the development of prostate cancer. It is thought that changes in the telomeres may be one of the first steps that occur as a cell progresses to become cancerous. Studying and characterizing these changes may give us a way to identify patients who are at risk of developing prostate cancer, so that these patients can be carefully monitored and treated. Future cancer prevention strategies may hinge on our ability to reverse some of these early changes.

Non-invasive monitoring of tumour progression in the Shionogi tumour model for prostate cancer
Dr. Donald T. Yapp PhD, BC Cancer Agency

Recent evidence suggests that oxygen levels within prostate cancer may reflect its aggressiveness. Also, it is believed that low oxygen levels within cancers may make them resistant to common treatments such as radiation and chemotherapy. Dr. Yapp proposes a novel non-invasive method of measuring oxygen levels within a mouse model of prostate cancer over time. This method relies on an intravenous compound called EF5 in conjunction with an imaging technology such as positron emission tomography (PET) or magnetic resonance spectroscopy (MRS). If successful, this technology could translate into better understanding and detection of when prostate cancer becomes aggressive as well as a more rational approach to its treatment.

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