P53 Activation as Novel Therapeutic Strategy for Acute Myelogenous Leukemia

P53 激活作为急性髓性白血病的新治疗策略

基本信息

批准号：
8499746
负责人：
MICHAEL ANDREEFF
金额：
$ 19.63万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
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：
2013-05-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8499746
关键词：
Acute Myelocytic Leukemia Affect American Society of Hematology Apoptosis Apoptosis Regulator Apoptotic Biological Markers Bone Marrow CXCL12 gene Cell Death Cell Nucleus Cells Clinical Clinical Protocols Communication Conduct Clinical Trials Confidential Information Cytolysis Cytoplasm Data Drug Kinetics Event FLT3 gene Funding Future GDF15 gene Genetic Transcription Goals Hematopoietic Histone Deacetylase Human In Vitro Induction of Apoptosis MDM2 gene Marrow Mediating Mus Nuclear Nuclear Export Patients Phase I Clinical Trials Plasma Production Reporting Residual Neoplasm Resistance Role Safety Signal Transduction Stromal Cell-Derived Factor 1 Stromal Cells TP53 gene Testing Therapeutic Therapeutic Effect Toxic effect Treatment outcome University of Texas M D Anderson Cancer Center analog base chemotherapeutic agent chemotherapy clinical efficacy combinatorial gene induction improved in vivo inhibitor/antagonist killings leukemia mutant novel novel therapeutic intervention novel therapeutics outcome forecast overexpression phase 1 study pre-clinical prognostic protective effect response restoration small molecule transcription factor tumor

项目摘要

The primary goal of this project is to improve treatment outcomes and cure rates of patients with acute myelogenous leukemia (AML) by developing novel, non-genotoxic therapeutic strategies that maximize the induction of leukemia cell apoptosis. TP53 is the master regulator of apoptosis that is frequently inactivated by overexpression of MDM2. Restoration of p53 activity by inhibition of MDM2-p53 interaction with non-genotoxic small molecule inhibitors (Nutlin-3a, RG7112, MI-63) dramatically increases cellular p53 levels and induces apoptosis. During the past funding period, we have generated pre-clinical and clinical evidence to support this concept. While much p53 in AML is localized in the cytoplasm, only nuclear p53 can function as transcription factor. Exportini (CRM1) is the major nuclear transporter of p53. Preliminary data suggest that CRM1 overexpression is associated with poor prognosis in AML. SINEs (selective inhibitors of nuclear export) are new, potent, irreversible and selective small molecule inhibitors of CRM1 [5, 6]. Our overall hypothesis is that nuclear retention of p53 by CRMI inhibition and non- genotoxic activation of p53 by inhibition of MDM2 will induce/enhance apoptosis in AML. in addition, we hypothesize that p53 is an important determinant of microenvironmental function. In Aim 1 we will test the hypothesis that blockade of p53 nuclear export by CRMI inhibition in AML enhances apoptosis induced by M0M2 inhibition. We reported that AML cells express p53 predominantly in the cytoplasm and hypothesize that CRMI inhibition results in nuclear accumulation and activity of p53, thereby enhancing p53-mediated transcription- dependent apoptosis. SINEs have minimal toxicities in normal human cells, including hematopoietic cells in vitro and in vivo. Our preliminary data show that SINEs induce cell death in AML in a p53-dependent manner. We will investigate if nuclear retention of p53 by CRMI inhibition synergizes with accumulation of p53 by MDM2 inhibition to induce apoptosis in AML. In Aim 2 we will investigate the role of p53 activation by MDM2 and CRMI inhibition in the bone marrow microenvironment. Bone marrow stromal cells protect AML cells from various anti-leukemic agents, but the MDM2 inhibitor Nutlin-3a or SINE KPT-185 kill AML cells even in the presence of

该项目的主要目标是改善急性骨髓性骨髓瘤患者的治疗结果和治愈率通过开发新颖的非基因毒性治疗策略来最大限度地诱导白血病（AML）细胞凋亡。 TP53 是细胞凋亡的主要调节因子，经常因 MDM2 的过度表达而失活。通过与非基因毒性小分子抑制剂抑制 MDM2-p53 相互作用来恢复 p53 活性 (Nutlin-3a、RG7112、MI-63) 显着增加细胞 p53 水平并诱导细胞凋亡。在过去的融资过程中在此期间，我们已经产生了临床前和临床证据来支持这一概念。虽然 AML 中的许多 p53 是定位于细胞质，只有核p53可以充当转录因子。 Exportini (CRM1) 是主要的 p53 的核转运蛋白。初步数据表明 CRM1 过度表达与不良预后相关反洗钱。 SINE（核输出选择性抑制剂）是一种新型、有效、不可逆的选择性小分子 CRM1 抑制剂 [5, 6]。我们的总体假设是，CRMI 抑制和非 p53 的核保留通过抑制 MDM2 来基因毒性激活 p53 将诱导/增强 AML 细胞凋亡。此外，我们假设 p53 是微环境功能的重要决定因素。在目标 1 中，我们将测试假设在 AML 中通过 CRMI 抑制来阻断 p53 核输出会增强由 M0M2 抑制。我们报道 AML 细胞主要在细胞质中表达 p53，并假设 CRMI 抑制导致 p53 的核积累和活性，从而增强 p53 介导的转录依赖性细胞凋亡。 SINE 对正常人体细胞（包括体外造血细胞）的毒性极小。体内。我们的初步数据表明，SINE 以 p53 依赖性方式诱导 AML 细胞死亡。我们将研究 CRMI 抑制对 p53 的核保留是否与 MDM2 抑制对 p53 的积累产生协同作用诱导 AML 细胞凋亡。在目标 2 中，我们将研究 MDM2 和 CRMI 抑制对 p53 激活的作用在骨髓微环境中。骨髓基质细胞保护 AML 细胞免受各种抗白血病药物的侵害但 MDM2 抑制剂 Nutlin-3a 或 SINE KPT-185 即使在存在以下物质的情况下也会杀死 AML 细胞