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Not all prostate cancers are life-threatening; in fact, many prostate cancers do not require aggressive treatment at all. Unfortunately, current tools do not allow oncologists to easily determine whether a given prostate cancer is likely to threaten a man’s life or not. Because the standard treatments for prostate cancer can cause serious side-effects, including impotence and incontinence, a test that would allow oncologists to better define which men need to be treated aggressively and therefore reduce the number of men who have to deal with these side-effects. Oncologists believe that subtle variations in genes that are involved in the production or function of male sex hormones (‘androgens’) may determine whether or not a prostate cancer progresses and becomes life-threatening. Dr. Levesque’s research team will look for specific genetic variations in prostate cancers taken from over 1800 men, and will then look to see whether certain genetic variations occur more frequently in those men whose cancers progressed more quickly. It is hoped that by identifying which men have prostate cancers that are more likely to become life-threatening, oncologists will be able better tailor treatments to individual patients, thus reducing the number of prostate cancers that are treated aggressively.
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Oncologists know that certain genes can be turned on or off (‘regulated’) inappropriately in many prostate cancers, and that inappropriate regulation of these genes can cause a more aggressive disease. Micro-RNA (miRNA) are small molecules that can turn other genes on or off, and it is believed that miRNA can play a role in prostate cancer progression by inappropriately regulating other genes. Two genes that are known to be very important for the progression of prostate cancer are called ERG and PTEN; it is believed that prostate cancers that have these genes altered are more aggressive and more likely to be lethal. Dr. Bismar’s research team will investigate whether certain miRNA molecules are turned on or off in prostate cancers that have alterations in the ERG and PTEN genes versus those prostate cancers in which the ERG and PTEN genes are normal. These studies will increase our basic understanding of how prostate cancers develop and progress, and will allow oncologists to better predict which patients are at the highest risk of lethal disease, and thus require more aggressive treatments.
The genetic material (DNA) within a cell is supported by proteins known as histones. Scientists now know that histone proteins can be chemically modified in response to environmental factors such as diet, and that these modifications can alter whether specific genes are turned on or off. Unlike DNA mutations, however, chemical modifications of histone proteins are potentially reversible. The progression of prostate cancer is highly influenced by the actions of male sex hormones (‘androgens’), and researchers have found that a specific histone protein called H2A.Z can influence the actions of androgens, and thus may have an important role to play in the development of prostate cancer. Dr. Ausio’s research team will study if and how H2A.Z can modify the actions of androgens, and whether H2A.Z can alter the progression and survival of prostate cancer cells. Dr. Ausio’s group will also study whether H2A.Z is altered in different ways in prostate cancers cells that have stopped responding to androgens. Dr. Ausio’s research may open up new potential avenues for the treatment of prostate cancer, especially for men for whom androgen therapy has stopped working.
Many scientists now believe that prostate cancers arise from a very small collection of cells termed cancer ‘stem’ cells and that in order to eradicate a tumor, these stem cells must be killed. Unfortunately, it is also believed that these stem cells possess special properties that make them resistant to killing by traditional therapies, and very little is known about why this is the case. One possible explanation is that prostate cancer stem cells have developed mechanisms to avoid being detected by a man’s immune system. If this is the case, then it may be possible to better identify these stem cells and ultimately to develop strategies to better target these cells. Dr. Helgason’s research team will examine whether specific immunity genes are turned off in prostate cancer stem cells and whether prostate cancer stem cells from tumors located inside the prostate gland have different immunity genes turned on or off than prostate cancers that have spread outside of the prostate gland (‘metastasized’). Dr. Helgason’s work will shed light on the role of prostate cancer stem cells in the progression and spread of prostate cancer, and on why prostate cancer stem cells are resistant to therapies.
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Dr. Laurent Azoulay
Male sex hormones (‘androgens’) are important for the development and progression of prostate cancer. Androgen deprivation therapy (ADT), which involves treating men with drugs that block the production or function of androgens in prostate cancer cells, has traditionally been used only for men with advanced prostate cancer, but is now often used for men with less aggressive disease. It has been known for some time, however, that ADT increases the risk of a man developing cardiovascular side effects, including coronary heart disease and heart attack. There is also concern that ADT may increase the risk of stroke. Dr. Azoulay’s team will evaluate a database of nearly 44,000 men with prostate cancer, who either did or did not receive ADT, and will attempt to establish whether or not ADT increases the risk of stroke. This large research study will establish whether ADT increases the risk of stroke, and if so, will help oncologists better structure treatments for men who are already at high risk for stroke.
When prostate cancer is confined to the prostate gland, it can often be cured by surgery or by radiation therapy. When it has spread outside of the prostate (‘metastasized’), however, it is often treated with drugs that block the effects of male sex hormones (‘androgen deprivation therapy’; ADT). Unfortunately, resistance to ADT eventually develops, at which point men can only be treated with a drug called docetaxel, though resistance to docetaxel eventually develops. Dr. Tang’s research team will investigate the mechanisms that cause docetaxel resistance, which may help to improve treatments for men with ADT-resistant prostate cancer. Specifically, Dr. Tang will investigate a gene called ABCC2, which functions as a molecular ‘pump’, removing docetaxel from the cancer cell. ABCC2 appears be turned on only in prostate cancer ‘stem’ cells, which are a small group of cells that are believed to be where prostate cancers originate. Dr. Tang’s group will examine the levels of ABCC2 in different prostate cancers and determine whether ABCC2 levels are higher in more aggressive prostate cancers. In addition, Dr. Tang’s group will use molecular tools to turn the ABCC2 gene on or off in prostate cancer cells and evaluate whether this affects the ability of docetaxel to kill the cells. The results of Dr. Tang’s research may open up new avenues for treating prostate cancers that have become resistant to ADT and to docetaxel.
One of the major challenges faced by oncologists is to identify men with prostate cancers that are likely to re-occur after surgery. Scientists believe that by studying the genetic makeup of prostate cancers, they may be able to identify molecular ‘biomarkers’ that could predict which cancers are destined to re-occur. Micro-RNAs (miRNAs) are a newly discovered class of small molecules that turn off specific genes, and it is thought that the pattern of miRNAs that are present in different tumors may predict for different outcomes. Dr. Yousef’s research team will use state-of-the-art molecular techniques to profile the pattern of miRNAs that are present in prostate cancers taken from men who had either early, intermediate, or no relapse. In follow-up experiments, Dr. Yousef’s group will determine whether these miRNA can alter the growth, survival, and progression of prostate cancer cells. These studies will help to identify men who are at the highest risk of reoccurrence, which may ultimately allow oncologists to better tailor their treatments to individual men