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SV 40可以作为共同致癌物的病因恶性 间皮瘤（MM）和AKT，细胞存活信号的关键介质，经常被激活，在这个过程中， 疾病人类肿瘤常表现出NF 2肿瘤抑制基因（TSG）的突变。此外，委员会认为， 编码TSG产物p16（INK 4a）和p14（ARF）的INK 4a/ARF基因座的纯合缺失， 尽管p16（INK 4a）与p14（ARF）在MM中的相对作用 发病机制尚未阐明。我们的假设是，这三个TSG和 SV 40和AKT癌蛋白的表达代表了间皮细胞生理学中的关键紊乱， 共同促进MM的发展。了解MM的分子发病机制， 在这种恶性肿瘤中受到干扰的信号通路可能阐明了 治疗/预防干预，这是该项目的广泛、长期目标。具体目标 1）使用体外和体内试验，我们将确定NF 2表达的恢复是否可以抑制NF 2表达。 NF 2缺陷型MM细胞的生长和侵袭力。我们还将进行实验，以评估 腺病毒介导的NF 2和选择性PAK抑制剂表达的治疗潜力，以及 进一步阐明梅林功能的实验。2)使用各种鼠基因敲除模型，评估 Nf 2、p19（Arf）和p16（lnk 4a）失活对石棉诱导MM的相对贡献。分子 将对来自这些小鼠的肿瘤进行遗传表征，以确定要求 用于易感TSG的双等位基因失活和/或癌基因或其它TSG的协作。我们将 比较p16（lnk 4a）+/-、p14（Arf）+/-和双杂合子对石棉诱导的MM的易感性 Ink 4a/Arf+/-小鼠在相同的遗传背景。此外，确定SV 40 Tag/tag小鼠模型是否 自发和/或石棉治疗后易患MM。3)进一步表征 AKT在MM中的参与，并确定是否对AKT信号通路的药理学抑制 可以抑制MM细胞生长，并且如果将AKT途径抑制剂与化疗剂组合， 具有不同的作用模式导致增加的功效。该项目将提供重要的见解 关于MM发病机制中关键癌蛋白和TSG产物的参与， 根据项目1和核心B和C中人和仓鼠MM样本的可用性以及 来自项目2中进行的共致癌作用和信号传导工作。