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Pim 1 Protein Kinase in Regulating Stromal Cell Biology in Prostate Cancer

Pim 1 蛋白激酶调节前列腺癌基质细胞生物学

基本信息

批准号：
8855025
负责人：
Andrew S Kraft
金额：
$ 19.96万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8855025
关键词：
Angiogenic Factor Animal Model Biological Assay Biology CXCL12 gene Cancer Etiology Cell Differentiation process Cell Line Cell physiology Cells Cellular biology Cessation of life Chemistry Clinic Collagen Data Dependency Drops Epithelial Epithelial Cells Epithelial-Stromal Communication Extracellular Matrix Extracellular Matrix Proteins Feedback Fibroblasts Genetic Genetic Recombination Glycoproteins Goals Growth Growth Factor Human Immunohistochemistry Integration Host Factors Integrins Interleukin-6 Knock-out Label Laboratories Lead Malignant Neoplasms Malignant neoplasm of prostate Measures Mediating Medical Mesenchymal Messenger RNA Methods Modality Modeling Mus Myofibroblast Neoplasm Metastasis Normal Cell PDGFRB gene PIM1 gene Pharmaceutical Preparations Phase Phenotype Phosphotransferases Platelet-Derived Growth Factor Platelet-Derived Growth Factor Receptor Play Procedures Production Prostate Prostatic Neoplasms Protein Isoforms Protein Kinase Protein Secretion Proteins Regulation Research Design Research Personnel Role Serine Signal Transduction Signal Transduction Pathway South Carolina Stromal Cells Stromal Neoplasm Testing Threonine Tissue Microarray Transforming Growth Factor beta Tumor Cell Line Universities Work angiogenesis base cancer therapy cell motility cell type human migration inhibitor/antagonist men migration mortality neoplastic cell novel novel therapeutic intervention overexpression periostin phase I trial prostate cancer cell public health relevance receptor research study small molecule transdifferentiation tumor tumor growth tumor progression tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer (PCa) epithelial cells have a critically important interaction with the surrounding tumor stromal microenvironment, and this feedback relationship stimulates PCa progression and metastasis. PCa stroma is composed of activated myofibroblasts that produce growth, angiogenesis, migration factors, and extracellular matrix, all of which contribute to tumor invasiveness. Disrupting this mutual-dependency tumor stromal-epithelial interaction leads to marked inhibition of tumor growth and blocks metastasis. Investigators in the Kraft laboratory at the Medical University of South Carolina have discovered that the PIM1 serine-threonine protein, known to be elevated in prostate cancer, is significantly increased in human prostate stromal cells and plays an important role in controlling fiibroblast cell biology. Increasing the level of PIM1 kinase in a normal prostate fibroblast cell line leads t the transdifferentiation of these normal cells to activated myofibroblasts, followed by the increase in the PDGF receptor and secretion of multiple factors that play a critical role in stimulating tumor growth. Further, these PIM activated myofibroblasts are capable of markedly stimulating the growth and migration of human prostate epithelial cells. These exciting results lead to the unique hypothesis that activated PIM1 kinase plays an important role in transdifferentiation of prostate fibroblast cells potentially controlling prostate cancer growth an migration. This hypothesis suggests that small molecule PIM inhibitory compounds in phase I trials and available to the Kraft laboratory have the potential to interrupt this epithelial:stroma feedback relationship and block the growth of these tumors. The specific aims will evaluate this hypothesis by: 1) determining whether increases in PIM1 in freshly isolated cancer associated fibroblasts drive and section of growth and migration factors and whether this can be inhibited by drugs which block the PIM kinase; and 2) examining whether PIM1 overexpressing prostate myofibroblasts are capable of induced epithelial cell malignancy and tumor growth in animal models. The proposed study design will make use of a novel glycoprotein labelling procedure that employs "click" chemistry to measure the stromal secretome, and a subrenal capsular recombination assay in mice. These studies will employ novel small molecule PIM inhibitors developed by AstraZeneca and Genentech that are entering the clinic for cancer therapy. These studies will markedly increase the understanding of the role of PIM1 in prostate cancer fibroblast activity and develop the rationale for using PIM inhibitors as a potential method of interrupting stromal:epithelial interaction inhibiting prostate tumor growth.