Regulating Cancer-Associated Fibroblast Biology in Prostate Cancer
Abstract
There is an urgent need to both develop new approaches to the treatment of prostate cancer and identify biomarkers to measure their success. In prostate cancer, there is an essential and close interaction between the cancer and the cells that surround it. These fibroblast cells, called cancer associated fibroblasts (CAFs), do not act normally, but instead produce a myriad of growth and attachment factors that enhance progression of prostate cancer. Targeting enzymes with small molecule drugs that control this abnormal behavior is a novel and important approach to inhibiting cancer growth that will be investigated in this proposal. This research will lead to the development of new potential urine biomarkers that can measure the success of these targeted drugs. Analysis of human prostate samples demonstrates that a specific signaling pathway, the Pim1 kinase pathway, is elevated in the fibroblasts from human prostate tumors. Data from the Andrew S. Kraft laboratory and collaborators demonstrate that activation of this enzyme pathway leads to secretion of growth-promoting proteins from patient-derived prostate fibroblast cells and causes normal fibroblast cells to become growth-promoting cells mimicking CAFs. Currently, small molecule drugs that inhibit the Pim1 kinase pathway are in Phase I human clinical trials. These have been used by the Kraft laboratory to block the secretion of these proteins from fibroblast cells; this suggests that these drugs could be used to inhibit the ability of abnormal prostate fibroblast cells to support tumor growth. The applicant team, by measuring small protein particles secreted by these cells, demonstrates that proteins secreted by fibroblasts are found in the urine of cancer patients and change with the severity of the disease, suggesting the possibility that these changes could be used as biomarkers for CAF-targeted drugs. Dr. Kraft and colleagues have formulated the important hypothesis that Pim1 protein kinase plays an essential role in driving protein production in CAFs and suggests that Pim1 kinase small molecule inhibitors can block prostate cancer growth. The first goal of this proposal is to use novel technology to examine the landscape of proteins regulated by Pim1 in freshly isolated human prostate cancer fibroblasts and to assess the capacity of these agents to inhibit the ability of these cells to stimulate prostate cancer growth. The second goal of this proposal is to use changes in the proteins secreted by these fibroblasts to develop biomarkers of Pim1 inhibitor drug activity that can potentially be measured in the urine of cancer patients. Since these Pim1-inhibitory drugs have entered Phase I human clinical trials in both solid and liquid tumors, it is possible that a trial of these agents in this cancer could be undertaken and that these new biomarkers can be evaluated in human studies. These studies will accelerate and significantly advance the rational development of targeted agents that inhibit the activity of CAF cell function for the treatment of prostate cancer, and by measuring the scope of proteins secreted by these cells using novel technology, develop potential urine biomarkers of treatment success.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510512
Entities
People
- Andrew S Kraft
Organizations
- United States Army
- University of Arizona