TARGETING OF TYROSINE KINASE PATHWAYS IN PROSTATE CANCER

描述：前列腺癌抵抗化疗是由于低比例的 分裂的细胞，并寻求新的策略，也将诱导凋亡 在非分裂细胞中。这一目标可以通过抑制 最有希望的自分泌生长和存活所使用的信号通路 前列腺癌的因素，白细胞介素-6，表皮生长因子和催乳素。的信号传导 这些细胞因子集中于Jak酪氨酸激酶和Stat转录 因素 到目前为止，还没有发表的关于正常人或正常人中Jak-Stat信号传导的研究。 前列腺恶性肿瘤基于令人信服的新数据和新的初步 观察，我们建议测试中心假设，Jak 2酪氨酸 激酶和Stat 5转录因子介导抗凋亡细胞因子信号 在正常和恶性前列腺上皮细胞中。基因（敲除小鼠）， 分子/表观遗传学（腺病毒基因递送）和药理学方法 将继续进行。 具体目标1：采用显性阴性突变体的腺病毒转移， 评估细胞凋亡和生长抑制作用的特异性抑制， Jak 2酪氨酸激酶和Stat 5转录因子与前列腺癌的关系 细胞和肿瘤组织外植体的体外和人前列腺肿瘤模型中， vivo. 具体目标2：测试小鼠中Stat 5缺乏是否增强 去势诱导的细胞凋亡，并进行形态和功能 我们在前列腺中发现的特定上皮缺陷的表征 Stat 5缺陷小鼠的研究 具体目标3：检测Jak 2-Stat 5通路的药理学抑制剂是否 将在正常和恶性前列腺的器官培养物中诱导细胞凋亡， 一组在不同生长条件下的前列腺癌细胞系。 具体目标4：鉴定55 kDa短型的 Stat 5是唯一激活的人前列腺癌细胞系， 可移植的人CWR 22前列腺癌模型，并在功能上表征 其转录调控作用。 由于我们在Jak-Stat信号方面的经验，我们具有独特的资格 转导，前列腺生物学和癌症的背景，以及独特的研究 工具.我们希望确定抑制Jak-Stat信号的有效性 正常和恶性前列腺细胞的存活和生长。这项研究是 意义重大和重要，因为它将提供新的洞察力的作用， Jak 2-Stat 5通路在前列腺功能中的作用。更有效的治疗 战略可能是一个结果。

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.