Kallikrein Gene Variants In Prostate Cancer: Analysis Of Gene Regulation And Diagnostic/Prognostic Use
Funder
National Health and Medical Research Council
Funding Amount
$486,801.00
Summary
Prostate cancer is the most common male cancer in Australia. However, early detection through screening programs has proven challenging, and about 30% of the 10,000 new cases diagnosed annually already have advanced disease. Hence, there is a fundamental need for increased basic research in prostate cancer etiology (cause) and tumour biology, and a critical requirement for methods that will assist in earlier detection of the disease and predict progression. A family of proteins called kallikrein ....Prostate cancer is the most common male cancer in Australia. However, early detection through screening programs has proven challenging, and about 30% of the 10,000 new cases diagnosed annually already have advanced disease. Hence, there is a fundamental need for increased basic research in prostate cancer etiology (cause) and tumour biology, and a critical requirement for methods that will assist in earlier detection of the disease and predict progression. A family of proteins called kallikreins (including prostate specific antigen, PSA) are often associated with clinical features of prostate cancer. We will characterise genetic variants (polymorphisms) in kallikrein genes that are consistently over-produced in prostate cancer, and determine whether they cause more protein to be produced in cells grown in the laboratory and in tumour tissue, and-or give rise to different expression products or splice variants. We will use bioinformatics (computer programs) to characterise published kallikrein gene sequences and to examine them for genetic variants that might be related to changes in gene expression or to splice variants. We will then use a case-control study, involving 1200 men with prostate cancer and 1200 healthy men, to determine whether these gene variants are associated with an increased risk of prostate cancer or with clinical aspects of the disease. Finally, we will examine the functional significance of the gene variants. This project represents an important and novel combination of molecular biology with the study of clinical disease at the population level, in the relatively new field of molecular epidemiology. It will clarify the role of kallikrein gene variants in prostate cancer risk and progression. The technologies may ultimately prove useful clinically for diagnosis of prostate cancer or for monitoring of treatment and prognosis, and hopefully will assist in clinical decision-making.Read moreRead less
The Essential Role Of Androgen Receptor Signalling In Prostate Tumorigenesis
Funder
National Health and Medical Research Council
Funding Amount
$714,375.00
Summary
An urgent objective in prostate cancer clinical practice is to better predict disease course at diagnosis and to identify patients likely to develop metastatic (lethal) disease. We aim to identify clinically-relevant genes - gene pathways that are important in prostate cancer development and progression and which can be used to improve prediction of patient outcome. Prostate cancer management can be improved by tailoring treatments for individual patients.
Functional Analysis Of The Roles Of The Serine Protease Kallikrein 7 And Its Variant Isoform In Serous Ovarian Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$509,017.00
Summary
Ovarian cancer is the leading cause of death from gynaecological cancers with 1,200 women in Australia diagnosed with the disease in 2004, and 852 patients dying of ovarian cancer. The mortality rate has improved little over the last two decades with one of the major reasons being that ovarian cancer is often diagnosed at a late stage when cancer cells have spread into the abdomen or metastasised to other sites. The kallikrein family of serine proteases or enzymes is emerging as very useful diag ....Ovarian cancer is the leading cause of death from gynaecological cancers with 1,200 women in Australia diagnosed with the disease in 2004, and 852 patients dying of ovarian cancer. The mortality rate has improved little over the last two decades with one of the major reasons being that ovarian cancer is often diagnosed at a late stage when cancer cells have spread into the abdomen or metastasised to other sites. The kallikrein family of serine proteases or enzymes is emerging as very useful diagnostic or prognostic biomarkers for ovarian cancer as they often have higher levels in ovarian cancer tissue compared to the normal ovary. One of these enzymes is kallikrein 7, which is also involved in shedding of skin cells. Because of its involvement in skin, we hypothesise it may be playing a similar role in ovarian cancer and helping the cancer cells to detach from the ovary so they are free to move around the body to other sites. There are two different forms of kallikrein 7, a long form and a shorter form which is lacking a part that is crucial to enzymatic activity. While low levels of the short form have been found in normal ovary, very high levels of both forms were seen in ovarian cancer, especially the serous subtype which is the most common and most aggressive form of ovarian cancer. The aim of this project is to determine the function(s) of both forms of kallikrein 7 in ovarian cancer and to identify other molecules-proteins they are involved with. These findings will tell us if kallikrein 7 is involved in the spreading of ovarian cancer cells or metastasis and will lead to a better understanding of the development and progression of ovarian cancer. The finding from this study may also lead to better therapeutic approaches (ie blocking the action of Kallikrein 7), and-or markers to monitor ovarian cancer progression.Read moreRead less
Proteolytic And Non-proteolytic Roles For PSA And Related Kallikrein Serine Proteases In Prostate Cancer Progression
Funder
National Health and Medical Research Council
Funding Amount
$480,128.00
Summary
Prostate cancer is the most frequently occurring cancer in men in Western countries. Prostate cancer metastasis to bone and other organs is the painful end stage of this disease. The level of prostate specific antigen (PSA) in blood is often used as a marker of prostate cancer. PSA is one of 15 related enzymes in the kallikrein family of enzymes, which may be involved in breakdown of the tissue that surrounds cells in the prostate. As prostate cancer metastasis first requires spread from the pri ....Prostate cancer is the most frequently occurring cancer in men in Western countries. Prostate cancer metastasis to bone and other organs is the painful end stage of this disease. The level of prostate specific antigen (PSA) in blood is often used as a marker of prostate cancer. PSA is one of 15 related enzymes in the kallikrein family of enzymes, which may be involved in breakdown of the tissue that surrounds cells in the prostate. As prostate cancer metastasis first requires spread from the primary tumour and out of the prostate, it is possible that high production of these kallikrein enzymes by prosttae cancer cells may increase the ability of these cells to metastasise. In previous work, we have studied prostate cancer cells that we have engineered to make the kallikreins, PSA and kallikrein 4. Those cells that make PSA or kallikrein 4 are more elongated in shape and are better able to move across a porous barrier. Another important change is that these cells stop producing a protein that is usually found on the surface of these cells and is important for helping cells to stay attached to each other. When this protein is lost, these tumour cells no longer stay attached to each other and are more likely to move out of the prostate and spread into other parts of the body. The changes we observed in the cells that produce PSA and kallikrein 4 are typical of these more aggressive cancer cells. In this project, we will look at how PSA and kallikrein 4 cause the cells to undergo these changes. The majority of prostate cancer deaths arise from cancer that has spread from the primary tumour and out of the prostate capsule. This project aims to further understand the causes of prostate cancer spread and metastasis. This is a vital research priority if we are to address the mortality associated with prostate cancer metastasis and may lead to new treatment approaches for advanced metastic prostate cancer.Read moreRead less