TARGETING OF TYROSINE KINASE PATHWAYS IN PROSTATE CANCER

点击翻译按钮获取中文摘要

DESCRIPTION: Prostate carcinomas resist chemotherapy due to a low fraction of dividing cells, and new strategies are sought that also will induce apoptosis in non-dividing cells. This goal might be achieved through inhibition of signaling pathways used by the most promising autocrine growth and survival factors for prostate cancer, interleukin-6, EGF and prolactin. Signaling by these cytokines converge on Jak tyrosine kinases and Stat transcription factors. To date there are no published studies on Jak-Stat signaling in normal or malignant prostate. Based on compelling new data and novel preliminary observations, we propose to test the central hypothesis that Jak2 tyrosine kinase and Stat5 transcription factors mediate anti-apoptotic cytokine signals in normal and malignant prostate epithelial cells. Genetic (knockout mice), molecular/epigenetic (adenoviral gene delivery), and pharmacological approaches will be continued. Specific Aim 1: Employ adenoviral transfer of dominant-negative mutants to assess the apoptotic and growth-inhibitory effect of specific suppression of Jak2 tyrosine kinase and Stat5 transcription factors in human prostate cancer cells and tumor tissue explants in vitro and in human prostate tumor models in vivo. Specific Aim 2: Test whether Stat5 deficiency in mice enhances castration-induced apoptosis, and perform a morphological and functional characterization of specific epithelial defects we have discovered in prostates of Stat5-deficient mice. Specific Aim 3: Test whether pharmacologic inhibitors of the Jak2-Stat5 pathway will induce apoptosis in organ cultures of normal and malignant prostate and in a panel of prostate cancer cell lines under various growth conditions. Specific Aim 4: Identify the molecular structure of a 55 kDa short form of Stat5 that is uniquely activated inhuman prostate cancer cell lines and in the transplantable human CWR22 prostate cancer model, and functionally characterize its transcription regulatory effects. We are uniquely qualified due to our experience with Jak-Stat signal transduction, background in prostate biology and cancer, and unique research tools. We expect to determine the efficacy of suppression of Jak-Stat signals on survival and growth of normal and malignant prostate cells. The research is significant and important because it will provide novel insight into the roles of Jak2-Stat5 pathways in prostate function. More effective therapeutic strategies could be a result.