Tyrosine Kinases and Prostate Cancer

酪氨酸激酶和前列腺癌

• 批准号: 8043744
• 负责人: Hsing-Jien Kung
• 金额: $ 8.76万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-30 至 2011-03-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8043744
• 关键词: Androgen Receptor; Androgens; Apoptosis; Apoptotic; Autophagocytosis; Cancer Biology; Cessation of life; Complex; Cytokine Receptors; Data; Development; Etiology; Evolution; Funding; G-Protein-Coupled Receptors; Grant; Growth; Laboratory Finding; Malignant neoplasm of prostate; Neuropeptides; Neurosecretory Systems; Oncogenic; PTK2 gene; Phosphotransferases; Process; Prostate; Protein Tyrosine Kinase; Reagent; Receptor Protein-Tyrosine Kinases; Role; Signal Transduction; Site; Testing; Therapeutic Intervention; Tyrosine Kinase Inhibitor; Work; abstracting; base; cancer cell; cell killing; design; effective therapy; hormone refractory prostate cancer; in vivo; inhibitor/antagonist; innovation; kinase inhibitor; mouse model; novel; prostate carcinogenesis; src-Family Kinases; therapeutic target; tumorigenesis

ABSTRACT This proposal ¿ tyrosine kinases and prostate cancer¿ began in 1998 with the development of tyrosine kinase display approach and the first comprehensive tyrosine kinase profile of prostate cancer cells. In the ensuing years, tyrosine kinases involved in neuroendocrine differentiation and androgen independence were identified and the processes characterized. This led to the discovery of a complex of tyrosine kinases Src, Etk and FAK (referred to as Src kinase complex) as a central integrator of signals emanating from tyrosine kinase receptor, cytokine receptor and G-protein coupled receptor. These tyrosine kinases present novel targets for potential therapeutic intervention. The present proposal is focused on prostate cancer biology and etiology, especially the involvement of Src/Etk tyrosine kinase complex in prostate carcinogenesis and androgen independence conversion. The potential of Src and Etk to serve as therapeutic targets will be explored. Our results in the past grant period contributed to the basic understanding of the roles of neuroendocrine differentiation and neuropeptide in androgen independent growth of prostate cancers, the involvement of Src kinase complex in inappropriate activation of androgen receptor, and the oncogenic role of Etk tyrosine kinase in prostate carcinogenesis. In addition, with our collaborators, we developed in vivo prostate cancer mouse models and potential inhibitors for the Src/Etk complex. Yet, the detailed mechanisms whereby Src kinase complex activates androgen receptor and the inhibitors of Src kinase complex induce cell killing remain largely unknown. Taking advantage of the discoveries and the reagents developed in the past grant period, the present proposal is designed to provide a better understanding of the mechanisms whereby Src tyrosine kinase complex activates androgen receptor and protects prostate cancer cells from autophagic and apoptotic death. Project Narrative One of the most troubling aspects of prostate cancer is its evolution to androgen independence, to which no effective treatment has been developed. The present proposal deals directly with the mechanisms of this evolution and has identified several key tyrosine kinases involved in this process. In addition, this proposal will provide important information concerning the mechanisms of cell killing by tyrosine kinase inhibitors and test the potential benefits of using these inhibitors in treating prostate cancers.

摘要 这项提案<$酪氨酸激酶和前列腺癌<$<$开始于1998年与酪氨酸的发展 激酶展示方法和第一个全面的前列腺癌细胞酪氨酸激酶谱。在 随后几年，酪氨酸激酶参与神经内分泌分化和雄激素非依赖性 并对过程进行了表征。这导致了酪氨酸激酶复合物的发现 Src、Etk和FAK（称为Src激酶复合物）作为从细胞中发出的信号的中心整合物， 酪氨酸激酶受体、细胞因子受体和G蛋白偶联受体。这些酪氨酸激酶 为潜在的治疗干预提供了新的靶点。目前的建议集中在前列腺 癌症生物学和病因学，特别是Src/Etk酪氨酸激酶复合物在前列腺中的参与 致癌和雄激素非依赖性转换。Src和Etk作为 将探索治疗靶点。我们在过去的赠款期间的结果有助于基本的 了解神经内分泌分化和神经肽在雄激素非依赖性 前列腺癌的生长，Src激酶复合物参与雄激素的不适当激活 受体，以及Etk酪氨酸激酶在前列腺癌发生中的致癌作用。此外，与我们的 与合作者，我们开发了体内前列腺癌小鼠模型和Src/Etk的潜在抑制剂， 复杂.然而，Src激酶复合物激活雄激素受体和雄激素受体的详细机制尚不清楚。 Src激酶复合物的抑制剂诱导的细胞杀伤仍然是未知的。利用了 根据过去授权期内的发现和开发的试剂，本提案旨在 更好地理解Src酪氨酸激酶复合物激活 雄激素受体和保护前列腺癌细胞免于自噬和凋亡死亡。项目叙述 前列腺癌最令人不安的方面之一是其向雄激素非依赖性的演变， 目前还没有有效的治疗方法。本提案直接涉及 这种演变的机制，并确定了几个关键的酪氨酸激酶参与这一进程。 过程此外，这项建议还将提供关于下列机制的重要信息： 酪氨酸激酶抑制剂的细胞杀伤作用，并测试使用这些抑制剂在 治疗前列腺癌