Targeting AML with PI3K/AKT inhibitors and BH3-mimetics

使用 PI3K/AKT 抑制剂和 BH3 模拟物靶向 AML

• 批准号: 8785103
• 负责人: Steven Grant
• 金额: $ 46.15万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-14 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8785103
• 关键词: AKT inhibition; Achievement; Acute Myelocytic Leukemia; Animals; Apoptotic; BCL2 gene; Biological Models; Blast Cell; CD34 gene; Cells; Cessation of life; Colony-forming units; Development; Disease; Dominant-Negative Mutation; Down-Regulation; Drug resistance; Event; Exhibits; FLT3 gene; Family; Family member; Foundations; Genetic; Goals; Grant; Health; Hematopoietic; Hematopoietic stem cells; Human; IL3RA gene; Immunocompromised Host; In Vitro; Individual; 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; Relative (related person); Resistance; Specimen; Testing; Therapeutic; Time; Up-Regulation; base; cell growth; effective therapy; genetic regulatory protein; human FRAP1 protein; in vivo; inhibitor/antagonist; insight; killings; leukemia; leukemogenesis; mTOR Inhibitor; mimetics; mutant; novel; pro-apoptotic protein; progenitor; programs; response; small hairpin RNA; small molecule; stem; success; synergism; tool; treatment strategy; tumor

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）：难治性急性髓性白血病（AML）迫切需要新的治疗策略。凋亡调节蛋白Bcl-2家族和PI 3 K/AKT/mTOR和MEK/ERK通路的失调经常发生在AML中，并且越来越多的证据表明Bcl-2家族成员之间的相互作用，除了它们的相对丰度之外，在决定细胞命运中起关键作用。我们现在提出了一种基于机制的抗白血病策略，将PI 3 K/mTOR抑制剂与BH 3模拟物ABT-737/263相结合，其中这三种重要的存活途径被协调破坏。这种方法利用了我们最近的发现，即在AML中，与其他肿瘤类型相反，PI 3 K/mTOR抑制剂与其他AKT通路拮抗剂不同，抑制AKT和ERK。在BH 3-模拟物的存在下，这导致前-（例如，Bim，巴克）和抗（例如，Mcl-1，Bcl-2/xL）凋亡蛋白，以及它们表达的扰动（例如，Mcl-1下调和Bim上调）。在具体目标#1中，我们将采用遗传策略（例如，Bim AKT或ERK磷酸化突变体，组成型活性或激酶死亡的AKT或MEK突变体）来检验我们的假设，即协同作用除了来自Mcl-1下调外，还来自于从Mcl-1/Bcl- 2/xL的抑制影响释放上调的Bim（以及巴克）。在特定目标2中，我们将测试以下假设：协同相互作用也会发生在原发性、遗传定义的AML标本中，并且类似的机制将起作用。我们还将检验PI 3 K/AKT通路突变，特别是基础AKT激活状态，可以预测这种疾病的易感性的假设。 战略在具体目标#3中，我们将检验PI 3 K/mTOR抑制剂和BH 3模拟物单独靶向原始白血病起始细胞（例如，CD 34 +/CD 38-/CD 123+）将协同相互作用以根除这种经典耐药群体。我们将 还首次表征了这些细胞中的AKT和ERK激活。在具体目标#4中，将采用多种体内全身性AML模型系统将体外结果外推至完整动物，并确定抗白血病协同作用是否存在相似机制。这些目标的实现将为开发和实施PI 3 K通路抑制剂/BH 3模拟抗白血病策略提供所需的理论基础，该策略代表了第一个协调中断三个相互作用的白血病相关通路的策略。它还可能有助于验证药效学反应决定因素，并确定最有可能从该策略中获益的个体AML患者。