Targeting AML with PI3K/AKT inhibitors and BH3-mimetics

使用 PI3K/AKT 抑制剂和 BH3 模拟物靶向 AML

基本信息

批准号：
9195615
负责人：
Steven Grant
金额：
$ 28.48万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-14 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9195615
关键词：
AKT inhibition Achievement Acute Myelocytic Leukemia Animals Apoptotic BCL2 gene BIM Bcl-2-binding protein Biological Models Blast Cell CD34 gene Cells Cessation of life Characteristics Colony-forming units Development Disease Dominant-Negative Mutation Down-Regulation Drug resistance Event Exhibits FLT3 gene FRAP1 gene Family Family member Foundations Genetic Goals Grant Hematopoietic Hematopoietic stem cells Human IL3RA gene Immunocompromised Host In Vitro Individual Interruption Lead Lesion Leukemic Cell MAPK3 gene MEKs Malignant Neoplasms Mediating Modeling Mus Mutation Myelogenous Myeloid Leukemia New Agents PI3K/AKT PTEN gene Pathogenesis Pathway interactions Patients Pharmacodynamics Phase I/II Trial Phosphorylation Phosphotransferases Physiological Play Population Predisposition Principal Investigator Protein Family Proteins Proto-Oncogene Proteins c-akt Refractory Regimen Resistance Specimen Testing Therapeutic Time Up-Regulation base cell growth effective therapy genetic regulatory protein in vivo individual patient inhibitor/antagonist insight killings leukemia leukemogenesis mTOR Inhibitor mimetics mutant novel pro-apoptotic protein progenitor programs public health relevance response small hairpin RNA small molecule stem success synergism tool treatment strategy tumor

项目摘要

DESCRIPTION (provided by applicant): New treatment strategies for refractory acute myelogenous leukemia (AML) are urgently needed. Dysregulation of the Bcl-2 family of apoptotic regulatory proteins and the PI3K/AKT/mTOR and MEK/ERK pathways occurs frequently in AML, and accumulating evidence indicates that interactions between Bcl-2 family members, in addition to their relative abundance, play key roles in determining cell fate. We now propose a mechanism-based anti-leukemic strategy combining PI3K/mTOR inhibitors with the BH3-mimetic ABT-737/263 in which these three important survival pathways are coordinately disrupted. This approach exploits our recent discovery that in AML, in contrast to other tumor types, PI3K/mTOR inhibitors, unlike other AKT pathway antagonists, inhibit both AKT and ERK. In the presence of BH3-mimetics, this leads to critical alterations in the association between pro-(e.g., Bim, Bak) and anti-(e.g., Mcl-1,Bcl-2/xL) apoptotic proteins, as well as perturbations in their expression (e.g., Mcl-1 down-regulation and Bim up-regulation). In Specific Aim #1, we will employ genetic strategies (e.g., Bim AKT or ERK phosphorylation mutants, constitutively active or kinase-dead AKT or MEK mutants) to test our hypothesis that synergism stems from, in addition to Mcl-1 down-regulation, unleashing of up-regulated Bim (as well as Bak) from the inhibitory influence of Mcl-1/Bcl- 2/xL. In Specific Aim 2, we will test the hypotheses that synergistic interactions will also occur in primary, genetically defined AML specimens, and that analogous mechanisms will be responsible. We will also test the hypothesis that PI3K/AKT pathway mutations, and particularly basal AKT activation status, can predict susceptibility to this strategy. In Specific Aim #3, we will test the hypothesis that PI3K/mTOR inhibitors and BH3-mimetics, which individually target primitive leukemia-initiating cells (e.g., CD34+/CD38-/CD123+), will interact synergistically to eradicate this classically resistant population. We will also characterize, for the first time, AKT and ERK activation in these cells. In Specific Aim #4, multiple in vivo systemic AML model systems will be employed to extrapolate in vitro findings to intact animals, and to determine whether similar mechanisms underlie anti-leukemic synergism. Fulfillment of these aims will provide the theoretical foundation needed to develop and implement a PI3K pathway inhibitor/BH3-mimetic anti-leukemic strategy, which represents the first to interrupt coordinately three mutually interactive leukemia-related pathways. It may also help to validate pharmacodynamic response determinants, and identify individual AML patients most likely to benefit from this strategy.

描述（由申请人提供）：迫切需要耐火性急性骨髓性白血病（AML）的新治疗策略。凋亡调节蛋白的Bcl-2家族和PI3K/AKT/MTOR和MEK/ERK途径的失调频率在AML中发生，并且积累证据表明Bcl-2家族成员之间的相互作用，除了其相对丰度，发挥关键确定细胞命运的作用。现在，我们提出了一种基于机制的抗白血病策略，将PI3K/MTOR抑制剂与BH3模拟ABT-737/263相结合，其中这三个重要的生存途径被协调。这种方法利用了我们最近的发现，与其他AKT途径拮抗剂不同，AML与其他肿瘤类型相比，PI3K/mTOR抑制剂抑制了AKT和ERK。在存在BH3-Mimetics的情况下，这会导致Pro-（例如BIM，BAK）和抗（例如Mcl-1，Bcl-2/XL）凋亡蛋白之间的关联以及在它们的表达（例如MCL-1下调和BIM上调）。在特定的目标＃1中，我们将采用遗传策略（例如BIM AKT或ERK磷酸化突变体，组成型活性或激酶已故AKT或MEK突变体）来检验我们的假设，即同义源于MCL-1下降，，从Mcl-1/bcl-2/XL的抑制作用中释放出上调的BIM（以及BAK）。在特定的目标2中，我们将测试在基本，遗传定义的AML样品中也将发生协同相互作用的假设，并且类似机制将负责。我们还将检验以下假设：PI3K/AKT途径突变，尤其是基础AKT激活状态，可以预测对此的敏感性战略。在特定的目标＃3中，我们将检验以下假设：PI3K/MTOR抑制剂和BH3-Mimetics分别靶向原始的白血病发射细胞（例如CD34+/CD38-/CD123+），将协同相互作用，以消除这种经典抵抗的人群。我们将还首次表征了这些细胞中的Akt和ERK激活。在特定的目标＃4中，将采用多个体内全身性AML模型系统来推断体外发现到完整的动物，并确定是否是抗白血病协同作用的类似机制。这些目标的实现将为开发和实施PI3K途径抑制剂/BH3模拟抗白血病策略提供理论基础，该策略代表了第一个中断协调三个相互交互性白血病相关的途径的基础。它还可能有助于验证药效反应决定因素，并确定最有可能从该策略中受益的个别AML患者。