Prostatic proteases: Functions and targets for treatment of prostate cancer
In the EU, prostate cancer affects the life of 1 of every 7 man and is one the leading causes of cancer deaths. Our long term goal is to improve the quality of life and reduce mortality of prostate cancer patients by revealing targetable mechanisms for aggressive prostate cancer for development of new therapies and by identifying novel prognostic markers, especially to discriminate cancers that need to be treated from indolent tumors that would not surface during the lifetime of the patient.
Our main research focus is on the functions and diagnostic potential of proteases, which play a significant role in virtually all stages of tumor progression, e.g., by modulating cellular signaling and extracellular environment. These include known prostate cancer markers, PSA and KLK2, for which we have developed small molecule- and peptide-based stimulators and inhibitors, aiming to slow down prostate cancer growth.
During recent years, we have broadened the focus to cover the roles of all human proteases, i.e., degradome, and protease inhibitors in growth, invasion and metastatic spread of prostate cancer cells. This involves development of novel patient-derived cell and tissue models. The cutting-edge approach used in the project is underpinned by a wide international collaborative network. With these studies we aim to identify novel prostate cancer markers and drug target molecules. One such example is trypsin-3, which stimulates prostate cancer cell invasion and for which we have identified (with David Fewer) a novel potent and selective inhibitor.
The role of glycodelin in cancer cell differentiation and reproductive biology
Glycodelin is a lipocalin family glycoprotein expressed mainly in reproductive tissues. In collaboration with William Yeung and Philip Chiu at University of Hong Kong we have established several reproduction related functions for glycodelin. Many of these functions are regulated by glycodelin's glycosylation. Thus, different glycoforms of glycodelin modulate a cascade of events spermatozoa undergoes before fertilization. Glycodelin also plays an important role in placental development and fetomaternal defense, which we have also found to be glycosylation dependent. Based on these studies, glycodelin is considered as one of the foremost examples of how glycosylation dictates the function(s) of a glycoprotein.
More recently we went on to show that glycodelin differentiates endometrial cancer cells towards a less aggressive phenotype, resulting in reduced tumor growth in a preclinical model. Interestingly, we also found that endometrial cancer glycodelin is differently glycosylated than that expressed in normal endometrium.
Highly validated immunoassays for cancer markers and for research in reproduction and endocrinology
The group has developed and carefully validated several sandwich-type in house immunoassays, using own monoclonal antibodies and time-resolved fluorometry based detection. These facilitate very sensitive detection and broad detection range. These, together with the assays developed at Professor emeritus Ulf-Håkan Stenman's research group, are used in several research projects relating to cancer, reproduction and endocrinological studies. The assays include those for glycodelin, IGFBP-1, IGFBP-3, semenogelin, all three different human trypsin-isoenzymes, SPINK1, and hCG and its subunits. We have also established assays for detection of specific glycoforms of proteins (using a combination of lectins and antibodies) and proximity-ligation based assays for active proteases (using a combination of peptides that bind only to the active form of proteases and specific antibody) and protease–inhibitor complexes. Most of the assays are available for collaborative projects.