Signal Transduction and Kinase Inhibition in CLL

CLL 中的信号转导和激酶抑制

• 批准号: 7117534
• 负责人: MICHAEL R GREVER
• 金额: $ 21.12万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-10 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7117534
• 关键词: apoptosis; clinical research; genetically modified animals; laboratory mouse; model; neoplasm /cancer; pharmacokinetics

In recent years numerous targeted therapies have been identified for therapeutic application in the treatment of cancer. While Chronic Lymphocytic Leukemia (CLL) is an obviously important clinical challenge, it is also is a disease well-suited for the development of novel agents, as readily available tumor cells facilitate validation of specific mechanisms of action in vivo. However, lacking from CLL therapeutic development have been CLL-specific targets and an appropriate in vivo model to test new therapies before transitioning to clinical investigation. Project 6 investigators in conjunction with others in the CLL Research Consortium (CRC) have actively developed multiple new therapies for CLL, including fludarabine, rituximab, and most recently, flavopiridol, as discussed in the previous application. We have further validated the Tcl-1 transgenic mouse model of CLL generated by Project 1 and advanced it into a tool that can be used for investigating new therapeutic agents for subsequent clinical development in CLL. This work and the interactions that have come forth through the CRC have resulted in 23 peer-reviewed publications. Here, we propose to continue active pre-clinical and translational development of new therapeutic agents in CLL. In Aim 1, we will expand our preliminary work with flavopiridol by performing detailed pharmacokinetic, pharmacodynamic, and pharmacogenomic studies as part of our planned Phase II clinical trial, including assessment of efficacy in patients with high risk genetic features such as del(17p13) and mutated p53. Relevant to the development of any effective agent is achieving an understanding of resistance mechanisms, which we will pursue using both CLL patient cells and the Tcl-1 transgenic mouse model of CLL. In Aim 2, we will continue pre-clinical development of the PDK1/Akt inhibitor OSU-03012, now approved for clinical development in CLL by the NCI RAID program, by a) examining the relationship of apoptosis induced by OSU-03012 to inhibition of PDK1/Akt in primary CLL cells; b) examining alternative signaling pathways inhibited by OSU-03012 and the mechanism(s) by which it induces caspase- and Bcl-2-independent apoptosis in CLL cells; and c) exploring synergy of OSU-03012 with other agents used for CLL treatment. In Aim 3, we will use the Tcl-1 transgenic mouse as a pre-clinical tool for developing CLL therapies by performing in vivo studies with flavopiridol, OSU-03012, and other novel therapies. These experiments will also incorporate limited pharmacokinetics and pharmacodynamics. Additionally, we will use the Tcl-1 mouse model to identify relevant mechanisms of drug resistance in vivo for therapies employed in the treatment of CLL. Each of these projects will be performed in collaboration with Projects 1-5 of the CRC, continuing our extensive interactions with these investigators. Overall, this project seeks to continue the comprehensive drug development effort by physician scientists, pharmacologists, and medicinal chemists at Ohio State University and other CRC institutions.

近年来，已经确定了用于治疗的治疗疗法的许多靶向疗法 癌症。慢性淋巴细胞性白血病（CLL）显然是一个重要的临床挑战，但也是 是一种非常适合开发新药的疾病，因为易于使用的肿瘤细胞有助于 验证体内作用的特定机制。但是，缺乏CLL治疗开发 已经是CLL特异性靶标，并且是适当的体内模型，用于测试新疗法，然后过渡到 临床研究。项目6调查人员与CLL研究联盟中的其他人结合 （CRC）积极开发了多种新疗法针对CLL，包括氟达拉滨，利妥昔单抗和大多数 最近，如先前的应用程序中讨论的，黄酮属醇。我们进一步验证了TCL-1转基因 项目1生成的CLL的鼠标模型，并将其推进到可以用于研究的工具中 新的治疗剂，用于随后的CLL临床发育。这项工作和互动 通过CRC出现，导致了23个经过同行评审的出版物。在这里，我们建议继续 新型治疗剂在CLL中的主动临床前和翻译发展。在AIM 1中，我们将扩展 我们通过详细的药代动力学，药效和 药物基因组学研究是我们计划的II期临床试验的一部分，包括评估疗效 具有高风险遗传特征的患者，例如DEL（17p13）和突变的p53。与发展有关 任何有效的代理人都在了解抵抗机制，我们将使用该机制来实现 CLL患者细胞和CLL的TCL-1转基因小鼠模型。在AIM 2中，我们将继续前临床前 PDK1/AKT抑制剂OSU-03012的开发，现已批准CLL的临床开发 NCI突袭计划，a）检查OSU-03012诱导的凋亡的关系 原代CLL细胞中的PDK1/AKT； b）检查OSU-03012抑制的替代信号通路和 它诱导CLL细胞中caspase-和Bcl-2独立凋亡的机制；和c）探索 OSU-03012的协同作用与其他用于CLL治疗的药物的协同作用。在AIM 3中，我们将使用TCL-1转基因 小鼠作为用于开发CLL疗法的临床前工具，该工具通过使用黄叶肽醇进行体内研究， OSU-03012和其他新型疗法。这些实验还将结合有限的药代动力学 和药效学。此外，我们将使用TCL-1鼠标模型来确定相关机制 用于治疗CLL的疗法的体内耐药性。这些项目中的每一个都将是 与CRC的项目1-5合作进行，继续我们与这些的广泛互动 调查人员。总体而言，该项目旨在继续医生的全面药物开发工作 俄亥俄州立大学和其他CRC机构的科学家，药理学家和药物学家。