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: 8605177
• 负责人: Steven Grant
• 金额: $ 27.63万
• 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 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8605177
• 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; 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; public health relevance; 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）：迫切需要针对难治性急性髓性白血病（AML）的新治疗策略。凋亡调节蛋白 Bcl-2 家族以及 PI3K/AKT/mTOR 和 MEK/ERK 通路的失调在 AML 中经常发生，越来越多的证据表明，除了相对丰度之外，Bcl-2 家族成员之间的相互作用也发挥着关键作用。决定细胞命运的作用。我们现在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，与其他肿瘤类型相比，PI3K/mTOR 抑制剂与其他 AKT 途径拮抗剂不同，可抑制 AKT 和 ERK。在 BH3 模拟物存在的情况下，这会导致促凋亡蛋白（例如 Bim、Bak）和抗凋亡蛋白（例如 Mcl-1、Bcl-2/xL）之间的关联发生重大改变，以及扰动它们的表达（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，即除了 Mcl-1 下调之外，协同作用还源自于此，从 Mcl-1/Bcl-2/xL 的抑制影响中释放上调的 Bim（以及 Bak）。在具体目标 2 中，我们将测试这样的假设：协同相互作用也将发生在主要的、基因定义的 AML 样本中，并且类似的机制将起作用。我们还将检验以下假设：PI3K/AKT 通路突变，特别是基础 AKT 激活状态，可以预测对此的易感性 战略。在具体目标 #3 中，我们将测试以下假设：PI3K/mTOR 抑制剂和 BH3 模拟物分别针对原始白血病起始细胞（例如 CD34+/CD38-/CD123+），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 AKT 和 ERK 的激活。在具体目标#4中，将采用多个体内系统性AML模型系统将体外研究结果外推到完整动物，并确定类似的机制是否是抗白血病协同作用的基础。这些目标的实现将为开发和实施 PI3K 通路抑制剂/BH3 模拟抗白血病策略提供所需的理论基础，该策略代表着第一个协调中断三个相互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反应决定因素，并确定最有可能从该策略中受益的个体 AML 患者。