Coagulation proteinases, proteinase-activated receptors and prostate cancer progression
Dr. Morley D. Hollenberg, University of Calgary Cumming School of Medicine
Eric Hyndman, Prostate Cancer Centre, Rocky View Hospital
Lead Investigator Bio:
Dr. Hollenberg is a Doctoral trained physician with an MSc (chemistry) from the University of Manitoba, a D. Phil. (Pharmacology from the University of Oxford) and an MD from Johns Hopkins University School of Medicine. His Medical Internship at the Johns Hopkins Hospital was followed by a Research Fellowship in the Department of Pharmacology & Therapeutics at Johns Hopkins, working on the molecular pharmacology of receptors for insulin and epidermal growth factor. He was recruited to the University of Calgary Faculty of Medicine in 1979, as the head of the Department of Pharmacology & Therapeutics, serving as Department Head from 1979 to 1989, and concurrently as the Chair of the Endocrine Research Group. Currently, he is Co-Director of the University of Calgary Cumming School of Medicine MD-PhD-MSc Leaders in Medicine programme. With continued CIHR funding since 1979, Dr. Hollenberg is a Principal Investigator for projects dealing with the molecular pharmacology of growth factor and G-protein-coupled receptors that are involved in diseases ranging from arthritis to colitis and prostate cancer. With over 19,000 citations to date and between 50-100 downloads/week (Research Gate), Dr. Hollenberg’s work was ranked in the Thompson Reuters 2014 top 1% of research citations in pharmacology world-wide, with a listing in ‘The World’s Most Influential Scientific Minds: 2014’ (ScienceWatch.com). A main focus in his lab is on the mechanisms whereby microenvironment proteinases drive inflammatory disease and cancer.
The blood clotting enzyme, thrombin, is known to stimulate cancer cell invasion by digesting and activating a cell surface tumor ‘switch’ receptor named PAR1. PAR1 is known to be increased in prostate cancer, leading to reduced patient survival. Although thrombin inhibitors have been used with limited success to treat cancer, we propose that a combined approach that blocks both thrombin and its target receptor PAR1 will succeed in stopping prostate cancer cell spread. We will test this idea by using thrombin and PAR inhibitors alone and in combination on human cell lines derived from castrate resistant prostate metastases (PC3 and DU145) and androgen-dependent (LNCaP) prostate cancer in both test-tube and in live animals experiments. In these cells we will also eliminate the production of PAR1 to evaluate their tumor-producing properties without this thrombin target. Our dual approach using both pharmacological blockade as well as genetic deletion will further our understanding of PARs and thrombin action in prostate cancer while potentially enabling a new way to treat this disease.
Coagulation and tumorigenesis are tightly linked (PMID19285272;-PMID:23452745)**, partly by activating proteinase-activated-receptors(PARs), which drive tumorigenesis(PMID:9701242;12637343; 21557443). We have 1. identified functional PARs 1&2 in the prostate-cancer-derived PC3, DU145 and LNCaP cells we will use and 2. found that matrix-metalloproteinase-MMP2, which is PAR-up-regulated in PC3s (PMID:15162383), can selectively (vs MMP1) regulate PARs1&2 by an autocrine mechanism. Thus, PARs and their activating proteinases can trigger a vicious tumorigenic-cycle via autocrine-tumour-promoting mechanisms (PAR-activation>>MMP-upregulation>>increased PAR-autocrine-activation). We hypothesize that using proteinase inhibitors along with PAR1/2 antagonists will provide a novel treatment for prostate cancer. We aim to use wild-type and CRISPR-PAR-null cells to explore cell migration/metastasis/invasion both in-vitro (Hollenberg) and in-vivo (collaboratively:with Addison,Guns): Aim.1: In Vitro, measure cell migration and transwell invasion of wild-type and PAR1/2-null cells. Aim.2: In Vivo, monitor growth/invasion/metastasis of wild-type and PAR1/2-null cells in mouse xenograft models. Aim.3): Pharmacological Profiling, determine if PAR1/PAR2-antagonists and/or inhibitors of PAR-activating proteinases acting alone or together block prostate tumour cell invasion/metastasis using both in vitro and in vivo approaches. We anticipate that combined inhibitors (for PARs-plus-proteinases) will synergistically block tumour cell invasion/metastasis both in vitro and in vivo, thus identifying a new strategy for treating prostate cancer.**REFERENCES:designated by PubMed ID numbers(PMIDs).
Impact on prostate cancer patients:
The results will evaluate the validity of a new therapeutic target to diminish prostate cancer initiation, invasion, metastasis and growth in the bones.