Research Grants 2005
Funded in March 2006, and executed in 2006-07 and 2007-08, based upon panel decisions communicated to each researcher
Enzymology of the Prostate Cancer Biomarker alpha-Methylacyl-CoA Racemase
Dr. Stephen Bearne BSc.H., PhD, MD, Dalhousie University
(AMACR (Alpha-MethylAcyl-CoA Racemase) is an enzyme, which is encoded by a gene that is overexpressed in prostate cancer cells, but not in normal ones. To date, little is known about the enzyme’s precise role in prostate cancer or whether inhibiting it might help kill prostate cancer cells. Dr. Bearne’s group will purify the enzyme from rats in order to obtain sufficient quantities for study. Rat AMACR is very similar to human AMACR. They will then develop an assay for detecting AMACR, and screen for compounds that may inhibit or inactivate it. The detection assay will aid future diagnosis of prostate cancer (e.g. from biopsies of prostate tissue). The inhibitors/inactivators will be used to further our understanding of prostate cancer biology, and may provide the platform for new treatments of prostate cancer.
Genetically controlled OAS activity influences apoptosis of prostate cancer cells
Dr. Vagn Bonnevle-Nielsen MD, PhD, University of British Columbia
Cancerous and pre-cancerous cells in the prostate may either grow or undergo controlled self-destruction (apoptosis). The balance between these paths may determine which men do and don’t develop detectable prostate cancer. RNaseL is an enzyme that affects cell growth and apoptosis. Low levels of it are linked to Hereditary Prostate Cancer. However, RNaseL is regulated by an enzyme called 2’5’-oligoadenylate synthetase (2’5’AS), which itself is encoded by a gene called OAS1. Different variants of the OAS1 gene lead to different levels of 2’5’AS, which may alter RNaseL and thus alter the balance between cell growth and apoptosis. Ultimately this may determine the fate of prostate cancer cells. Dr. Bonnevle-Nielsen will study the effect of different OAS1 variants on cell growth and apoptosis in prostate cancer cells in the laboratory. This research may help determine which men are at increased genetic risk of prostate cancer, and may suggest new therapies by targeting the OAS1 – 2’5’AS – RNaseL system.
Designing small hairpin Ranks to increase the sensitivity of prostate cancer cells to chemotherapeutic drugs
Dr. Gerardo Ferbeyre MD, PhD, University Of Montreal
Prostate Cancer cells generally contain abnormal genes. These genes are turned into substances called mRNA, which in turn are made into the proteins that drive the cancer cell. One anti-cancer strategy is to ‘knock-down’ the mRNA before it gets turned into a protein that the cancer cell needs to survive. This can be done by using a complimentary RNA to the targeted mRNA, called small interfering RNA (siRNA). However, this approach is limited by the fact that different cancer cells each contain many different abnormal mRNAs, so that simply targeting one of them may not succeed in controlling the cancer. Currently siRNA’s only target one mRNA each. Dr. Ferbeyre and his team have developed a new type of siRNA that can target 2 different mRNAs simultaneously. They will confirm that it is effective, and then use a special computer program to find more siRNA’s that target the same 2 mRNAs. In this way a library of bi-functional siRNA’s can be built. Using the novel siRNA’s will teach us more about how prostate cancer cells work, and may reveal some of their weaknesses, thus leading to improved treatments in the future.
3-Dimensional Structural and Functional Magnetic Resonance Imaging to Localize Intra-Prostatic Cancer
Dr. Masoom Haider MD, Hons B. Math, University Health Network
Even in prostate cancer, certain parts of the gland contain normal prostate tissue while others contain cancer cells. If treatment could be restricted to only the cancerous part of the gland, it could lead to fewer side effects. In order to achieve this, we must be able to visualize and distinguish the normal and cancerous parts of the prostate gland. Dr. Haider and his team will attempt to achieve this using Magnetic Resonance Imaging (MRI) of the prostate. MRI can provide information on prostate structure, blood flow and water diffusion. By optimally combining this information, it may be possible to accurately distinguish normal and cancerous areas of the prostate gland, using a non-invasive imaging technique. This could lead to improvements in treatment and in detecting recurrences afterwards.
Gene Translocations in Prostate Cancer: Clinical and Biological Significance
Dr. David Huntsman MD, FRCPC, FCCMG, BC Cancer Agency
Cancer cells often demonstrate abnormal mixing and merging of pairs of genes: these are known as ‘gene-fusions’. A new gene fusion has recently been discovered that is unique and specific to prostate cancer. The fusion may lead to one of the genes in it being over-expressed in prostate cancer. This discovery was made in a relatively small sample of prostate cancers. Dr. Huntsman and his team will confirm the presence of this gene-fusion in a much larger sample of prostate cancers, in order to determine its true frequency. They will also match their findings with the clinical outcome of the patients whose cancers are being studied, thus showing the importance of the ‘gene-fusion’ to the prognosis of men with prostate cancer. Finally they will assess whether overproduction of one of the genes in the fusion is important for prostate cancer cells grown in the laboratory. All these studies will increase our understanding of prostate cancer, leading to new diagnostic and treatment techniques.
Regulators of Prostate Cancer Immunogenicity
Dr. Wilfred Jefferies D.Phil, BSc, University of British Columbia
Prostate cancer is often only cured when it is still confined to the prostate gland, and has not already spread further. The immune system has an important role in detecting and limiting cancers, as they attempt to spread from their site of origin. It also aids in recovery from cancer. Unfortunately, prostate cancer cells can down-regulate important pathways that make them less noticeable to the human immune system, thus enabling them to grow and spread. Dr. Jefferies and his team have identified several of these pathways, and plan to manipulate them so as to augment the immune system when it comes into contact with such cancer cells. This may improve the effectiveness of current prostate cancer therapies.
Structure Based Drug Discovery against Novel Binding Pockets of Androgen Receptors
Dr. Steven Jones PhD, MSc, BSc, BC Cancer Agency – Genome Sciences
Prostate cancers often depend on hormones called androgens (e.g. testosterone) in their early stages, and initially respond well to drugs that block the receptors on cancer cells to which androgens bind. Unfortunately, with time, prostate cancers mutate their androgen receptors and become resistant to androgen-blockade. Dr. Jones and his team will use advanced computer programs to search the androgen receptor’s surface, in virtual reality, for new sites that will bind novel androgen blockers. These new blockers will be chosen from a ‘library’ of 3 million drug-like molecules that will be screened, again using state-of-the-art computer programming. The most promising molecules will be testing on prostate cancer cells in the laboratory. This research will use technology to accelerate the discovery of useful new drugs in the treatment of prostate cancer.
ERK MAPkinase targeting as Combined Modality Therapy for Prostate Cancer
Dr. Jan Jongstra PhD, MSc, University Health Network
The ERK-MAPkinase pathway is a biochemical-signaling system that promotes growth and survival in prostate cancer cells. Dr. Jongstra’s group have isolated a new inhibitor of this pathway, and shown that it potentiates the effect of radiation on the killing of prostate cancer cells. This is very promising, as radiation therapy is one of the main treatments for men with prostate cancer. A compound that makes the cancer more sensitive to radiation may lead to higher cure rates and/or shorter treatment courses. Dr. Jongstra will now test the new compound in mice that bear prostate cancers, which are being treated with radiation. This is an important step in assessing whether it may be a safe and useful compound to add to the radiation treatment of men with prostate cancer.
Targeting ER-bound transcription factors in prostate cancer
Dr. Claude Labrie MD, PhD, University of Laval
When cells undergo stress, a group of proteins (called Transcription Factors) travel to nucleus of the cell and activate a specific set of genes. These genes encode the proteins essential for the cell to survive the stress. Some of the transcription factors involved in stress responses belong to a family known as bZIP. Dr. Labrie will be studying a bZIP that is abundant in prostate cancer cells, called AIbZIP (Androgen-Induced bZIP). He and his team have observed that prostate cells with less bZIP grow more slowly. They will explore this further using molecules that stick to a critical region of AIbZIP, thus preventing its action at the cell nucleus in response to stress. The goal of this research is to weaken the natural defenses of prostate cancer cells, rendering them more sensitive to treatment.
Identification of novel tumor suppressor genes in prostate cancer
Dr. Jacques Lapointe MD, PhD, McGill University
Currently, there is not a solid way of predicting, at the time of diagnosis, which patient will do well and which one won't. It is known, however, that the genome of a cancer cell is not normal: the cancer cell looses "good" genes that prevent its multiplication and accumulates "bad" genes that encourage its growth. It is possible that the difference between an aggressive cancer and indolent one reflects differences in their genomes. Dr. Lapointe and his team are using a technique that measures very accurately thousands of genomic changes at a time in a large number of prostate tumors. It is hoped that they can identify the "good genes" that are lost during the cancer development. This work will provide a better understanding of the causes of prostate cancer and will lead to the development of better treatments.
The Impact of Neural Network Technology on the Prediction of Prostate Cancer
Ms. Gina Lockwood PhD, MSc, BA, University Health Network
At present, early detection of prostate cancer depends on finding raised blood levels of a substance called PSA (Prostatic Specific Antigen). If raised above a certain threshold, a biopsy of the prostate is performed. However not all such biopsies show cancer, hence improved methods of prediction are required to avoid unnecessary biopsies and the anxiety associated with them. Dr. Lockwood’s team will incorporate clinical information, in addition to PSA, from a large database of men with known prostate cancer. They will then use statistical methods, as well as two types of artificial intelligence computer programs (neural networks), to turn this extra information into a more accurate forecast of whether a prostate biopsy will show cancer or not. Once the best technique is determined, it will be tested independently on a second large database of men with known prostate cancer. This will help to validate it as a predictive tool. This research aims to help select better the men who would and would not benefit from a prostate-biopsy.
PSF Modulates Androgen Receptor Function in Human Prostate Cancer
Dr. Stephen Lye PhD, Bachelor’s Honours, Mount Sinai Hospital
Prostate cancers often depend on hormones called androgens (e.g. testosterone) in their early stages, and initially respond well to drugs that block the receptors on cancer cells to which androgens bind. Unfortunately, with time, many prostate cancers can activate the androgen receptor without androgens, nullifying the effect of the blocking drugs. This enables the cancers to progress, and represents a more aggressive type that responds poorly to treatment. Dr. Lye and his team have identified a protein called PSF, which appears to interact with the androgen receptors and blocks their ability to stimulate cancer cell growth. Their studies aim to measure the level of PSF in prostate cancer cells; confirm that PSF inhibits the androgen receptors actions, and determine the molecular mechanisms of this inhibition. The goal of this work is to develop new treatments for men whose prostate cancers are no longer responsive to traditional androgen-receptor blockade.
Does O-glycosylation post-translational modification of beta-catenin regulate its Oncogenic properties and prostate cancer
Dr. Sujata Persad PhD, MSc, BSc, McMaster University
ß-Catenin is found in cells, and helps them stick together. It also regulates the level of many different proteins in the cell, by traveling to the cell’s nucleus and activating certain genes that encode the proteins. When these proteins become expressed excessively, there is an increased risk of development and progression of cancer. Dr. Persad’s group recently found that ß-Catenin can be modified by having sugars added to it, in a process called ‘O-Glycosylation’. They also found that breast cancer cells had much more O-Glycosylation of ß-Catenin than normal breast cells. This may be because O-Glycosylation enables ß-Catenin to get into the cell nucleus more easily, leading to the production of excess proteins and eventually to cancer. Dr. Persad will examine this question in prostate cancer, yielding new insights into how this disease works and how it might be treated.
Advanced Molecular Diagnostics of Prostate Cancer Using ETS Fusion Gene
Dr. Jeremy Squire, MSc, BSc, PhD, Ontario Cancer Institute, University Health Network
Cancers frequently harbor abnormal genes and gene arrangements, including ‘gene-fusions’ – where genes are merged together. A new gene fusion called the ‘ETS family’ has recently been discovered as occurring only in prostate cancer. Because it is specific to prostate cancer, it can be used to develop diagnostic tests using blood or urine samples. This may ultimately lead to new and improved screening tests for prostate cancer in men, or to earlier detection of its recurrence after treatment. If a way can be found to block the formation of the ETS-gene fusion, this may even yield a new treatment for prostate cancer. Dr. Jeremy Squire and his team have already validated the discovery of the ETS-gene fusion, and detected new types of ETS fusions. Their goal is to bring this new knowledge into clinical practice as soon as possible, in order to improve detection, diagnosis and ultimately the treatment of prostate cancer.
Effect of a Low-carbohydrate Diet on Prostate Cancer in Vivo: Alterations in Biochemical Mechanisms Involving the Insulin and IGF axis
Dr. Vasundara Venkateswaran PhD, M.Phil, MSc, BSc, Sunnybrook & Women’s College Health Sciences Center
Both a high-fat intake and obesity have been linked with a higher incidence of, and mortality from, prostate cancer. High carbohydrate levels cause increased levels of the hormone insulin, which itself promotes fat storage. Diets rich in fatty acids may, in turn, contain carcinogens. There are associations between prostate cancer and the high insulin levels of a high-carbohydrate high-fat diet. The precise mechanisms behind this are not yet fully understood. Dr. Vasundara’s group will explore the hypothesis that a low-carbohydrate diet will result in lower insulin levels, which in turn will protect against the carcinogenic potential of a high-fat diet. It also addresses the general usefulness of low-carbohydrate diets in cancer prevention. Their findings will help to develop recommendations on population dietary changes that may lead to reductions in prostate cancer frequency and mortality.
Anti-angiogenic micro-surgery therapy of genetically engineered mouse prostate cancer monitored by 3-D power Doppler ultrasound
Dr. Jim W. Xuan PhD, MSci, Lawson Health Research Institute
Prostate cancer tumors require a blood supply to provide nutrients and to remove waste products. There is emerging evidence that tumors can be killed or shrunken by abolishing their blood-supply. This can be done with drugs or by microsurgery, in which the vessels feeding the tumor are cut. In order to study the value of this treatment strategy, a model is needed where prostate tumors can have their blood supply cut, and a technique is needed to visualize both the prostate tumor and its blood vessels. Dr. Xuan’s team has developed a mouse, which carries a prostate tumor. This tumor can be operated on, and have its blood supply cut, as described above. In order to visualize the very small vessels involved, they have developed an imaging technology called 3-D Power Doppler. This works using high frequency sound waves, and is an accurate and non-invasive way of visualizing tumors and their blood flow. This research aims to develop both new treatment techniques for prostate cancer and new imaging techniques for visualizing tumors and their blood supply.