Signal Transduction and Kinase Inhibition in CLL

近年来，已经确定了许多靶向疗法在治疗中的治疗应用 癌症。虽然慢性淋巴细胞白血病（CLL）是一个明显重要的临床挑战，但它也是一个重要的临床挑战。 是一种非常适合开发新药物的疾病，因为容易获得的肿瘤细胞有助于 体内特定作用机制的验证。然而，缺乏CLL治疗发展， 是CLL特异性靶点，也是在过渡到 临床研究项目6研究人员与CLL研究联盟的其他研究人员一起 (CRC)积极开发多种新的CLL疗法，包括氟达拉滨，利妥昔单抗， 最近，如在先前申请中所讨论的，Flavopiridol。我们进一步验证了Tcl-1转基因 CLL小鼠模型，并将其发展为可用于研究的工具 用于CLL后续临床开发的新治疗药物。这项工作和互动， 通过化学品审查委员会提出的建议已产生23篇同行评审的出版物。在此，我们建议继续 CLL中新治疗药物的积极临床前和转化开发。在目标1中，我们将扩大 我们的初步工作与flavopiridol进行详细的药物动力学，药效学， 药物基因组学研究作为我们计划的II期临床试验的一部分， 具有高风险遗传特征的患者，例如del（17 p13）和突变的p53。与发展有关的 任何一种有效的药物都能理解耐药机制，我们将继续使用 CLL患者细胞和CLL的Tcl-1转基因小鼠模型。在目标2中，我们将继续进行临床前 PDK 1/Akt抑制剂OSU-03012的开发，现已被批准用于CLL的临床开发。 a）检查OSU-03012诱导的细胞凋亡与细胞凋亡抑制的关系， B）检查由OSU-03012抑制的替代信号传导途径和由OSU-03012抑制的PDK 1/Akt; 其诱导CLL细胞中的半胱天冬酶和Bcl-2非依赖性凋亡的机制;以及 OSU-03012与用于CLL治疗的其它药剂的协同作用。在目标3中，我们将使用Tcl-1转基因 小鼠作为临床前工具，通过用flavopiridol进行体内研究来开发CLL疗法， OSU-03012和其他新疗法。这些实验还将纳入有限的药代动力学 和药效学。此外，我们将使用Tcl-1小鼠模型来确定 在CLL的治疗中使用的疗法的体内耐药性。每一个项目都将 与CRC的项目1-5合作进行，继续我们与这些项目的广泛互动。 investigators.总的来说，该项目旨在继续由医生进行全面的药物开发工作， 俄亥俄州州立大学和其他CRC机构的科学家、药理学家和药物化学家。

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.