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 分裂细胞，并寻求新的策略，也将诱导细胞凋亡 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生存所使用的信号通路 前列腺癌的致癌因素、白介素6、表皮生长因子和催乳素。信令方式 这些细胞因子聚集在JAK酪氨酸激酶和STAT转录上 各种因素。 到目前为止，还没有关于Jak-Stat信号在正常或 恶性前列腺癌。基于令人信服的新数据和新颖的初步 观察，我们建议检验JAK2酪氨酸的中心假设 激酶和Stat5转录因子介导的抗凋亡细胞因子信号 在正常和恶性前列腺上皮细胞中。遗传(基因敲除小鼠)， 分子/表观遗传学(腺病毒基因传递)和药理学方法 将会继续。 具体目标1：使用腺病毒转移显性-阴性突变体来 评估特异性抑制细胞凋亡和抑制生长的作用 JAK2酪氨酸激酶和Stat5转录因子在前列腺癌中的表达 细胞和肿瘤组织外植体的体外培养及人前列腺癌模型 活着。 特定目标2：测试小鼠缺乏Stat5是否会增强 去势诱导细胞凋亡，并在形态和功能上 我们在前列腺中发现的特定上皮缺陷的特征 STAT5基因缺陷的小鼠。 具体目标3：测试JAK2-Stat5通路的药理抑制剂 会诱导正常和恶性前列腺组织培养的细胞凋亡 一组不同生长条件下的前列腺癌细胞系。 具体目标4：确定55 kDa缩写形式的分子结构 STAT5是唯一被激活的非人类前列腺癌细胞系，在 可移植人CWR22前列腺癌模型的建立及功能鉴定 它的转录调控作用。 由于我们在Jak-Stat Signal方面的经验，我们具有独一无二的资格 转导、前列腺癌生物学背景和独特研究 工具。我们希望确定抑制JAK-Stat信号的有效性 对正常和恶性前列腺细胞的存活和生长的影响。这项研究是 重大而重要的，因为它将提供对角色的新见解 JAK2-Stat5通路在前列腺功能中的作用。更有效的治疗 战略可能就是一个结果。

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.