AKT AND TUMOR SUPPRESSOR PATHWAYS IN MESOTHELIOMA

间皮瘤中的 AKT 和肿瘤抑制途径

• 批准号: 7035624
• 负责人: Joseph R. Testa
• 金额: $ 39.33万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7035624
• 关键词: asbestos; athymic mouse; cocarcinogen; environment related neoplasm /cancer; enzyme activity; enzyme mechanism; focal adhesion kinase; gene environment interaction; genetically modified animals; hamsters; laboratory mouse; mesothelioma; molecular pathology; neoplasm /cancer genetics; neoplasm /cancer pharmacology; neoplastic process; oncogenes; oncogenic virus; serine threonine protein kinase; simian virus 40; transfection /expression vector; tumor suppressor genes; xenotransplantation

Recent work suggests that asbestos and SV40 can act as co-carcinogens in the etiology of malignant mesothelioma (MM) and that AKT, a critical mediator of cell survival signals, is frequently activated in this disease. Human MMs often exhibit mutation of the NF2 tumor suppressor gene (TSG). Furthermore, homozygous deletion of the INK4a/ARF locus, which encodes the TSG products p16(INK4a) and p14(ARF), is frequently observed, although the relative contribution of p16(INK4a) versus p14(ARF) in MM pathogenesis has not been elucidated. Our hypothesis is that alterations of these three TSGs and expression of SV40 and AKT oncoproteins represent key disturbances in mesothelial cell physiology that collectively contribute to the development of MM. Understanding the molecular pathogenesis of MM and signaling pathways perturbed in this malignancy may elucidate invaluable molecular targets for therapeutic/preventive intervention, which is the broad, long-term objective of this project. The specific aims are: 1) Using in vitro and in vivo assays, we will determine whether restoration of NF2 expression can inhibit the growth and invasiveness of NF2-deficient MM cells. We will also conduct experiments to evaluate the therapeutic potential of adenovirus-mediated expression of NF2 and selective PAK inhibitors, as well as experiments to further elucidate merlin's function. 2) Using various murine knockout models, evaluate the relative contribution of Nf2, p19(Arf), and p16(lnk4a) inactivation to induction of MM by asbestos. Molecular genetic characterization of tumors derived from these mice will be conducted to establish the requirement for biallelic inactivation of the predisposing TSG and/or cooperation of oncogenes or other TSGs. We will compare susceptibility to asbestos-induced MM in p16(lnk4a)+/-, p14(Arf)+/- and doubly heterozygous Ink4a/Arf+/- mice in the same genetic background. In addition, determine if a SV40 Tag/tag mouse model is predisposed to MM spontaneously and/or following treatment with asbestos. 3) Further characterize the involvement of AKT in MM and determine whether pharmacologic inhibition of the AKT signaling pathway can repress MM cell growth and if combining an AKT pathway inhibitor with chemotherapeutic agents having a different mode of action results in increased efficacy. This Project will provide important insights regarding the involvement of key oncoproteins and TSG products in the pathogenesis of MM and will benefit from the availability of human and hamster MM samples through Project 1 and Cores B and C as well as from co-carcinogenesis and signaling work conducted in Project 2.

最近的研究表明，石棉和 SV40 可作为恶性癌症病因学中的共致癌物。 间皮瘤 (MM) 中细胞存活信号的关键介质 AKT 在这种情况下经常被激活 疾病。人类 MM 经常表现出 NF2 肿瘤抑制基因 (TSG) 的突变。此外， INK4a/ARF 基因座的纯合缺失，该基因座编码 TSG 产物 p16(INK4a) 和 p14(ARF)， 经常观察到，尽管 p16(INK4a) 与 p14(ARF) 在 MM 中的相对贡献 发病机制尚未阐明。我们的假设是这三个 TSG 的改变和 SV40 和 AKT 癌蛋白的表达代表间皮细胞生理学的关键紊乱， 共同为MM的发展做出贡献。了解 MM 的分子发病机制和 这种恶性肿瘤中受到干扰的信号通路可能会阐明宝贵的分子靶标 治疗/预防干预，这是该项目的广泛、长期目标。具体目标 是：1）使用体外和体内测定，我们将确定恢复 NF2 表达是否可以抑制 NF2 缺陷的 MM 细胞的生长和侵袭性。我们还将进行实验来评估 腺病毒介导的 NF2 表达和选择性 PAK 抑制剂的治疗潜力，以及 进一步阐明merlin功能的实验。 2) 使用各种小鼠敲除模型，评估 Nf2、p19(Arf) 和 p16(lnk4a) 失活对石棉诱导 MM 的相对贡献。分子 将进行来自这些小鼠的肿瘤的遗传特征以确定要求 用于诱发 TSG 的双等位基因失活和/或癌基因或其他 TSG 的合作。我们将 比较 p16(lnk4a)+/-、p14(Arf)+/- 和双杂合子对石棉诱发 MM 的易感性 Ink4a/Arf+/- 小鼠具有相同的遗传背景。此外，确定 SV40 标签/标签鼠标型号是否为 自发地和/或接受石棉治疗后易患 MM。 3）进一步表征 AKT 参与 MM 并确定药物是否抑制 AKT 信号通路 如果将 AKT 通路抑制剂与化疗药物联合使用，可以抑制 MM 细胞生长 不同的作用方式会提高功效。该项目将提供重要的见解 关于关键癌蛋白和 TSG 产品参与 MM 发病机制的研究将受益 从人类和仓鼠 MM 样本的可用性通过项目 1 和核心 B 和 C 以及 来自项目 2 中进行的协同致癌和信号传导工作。