Targeting FOXM1 in chemo-resistant monocytic AML

靶向 FOXM1 治疗耐药单核细胞 AML

基本信息

批准号：
10438818
负责人：
ANDREI L GARTEL
金额：
$ 20.73万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10438818
关键词：
11q23 Acute Myelocytic Leukemia Acute leukemia Acute monocytic leukemia Acute respiratory failure Adult Antineoplastic Agents Apoptosis Biological Availability Blood Coagulation Disorders CASP3 gene Cell Line Cells ChIP-seq Characteristics Chemoresistance Clinical Cytarabine Cytogenetics Cytoplasm Data Disease remission Dose Drug Kinetics FOXM1 gene Family Genes Gingival Hyperplasia Individual KRAS2 gene Laboratory Research Leukemic Cell Libraries Life Expectancy Link Mammalian Cell Maximum Tolerated Dose Molecular Chaperones Monitor Monocytic leukemia Mus Mutate Mutation NPM1 gene Nature Neuraxis Nuclear Outcome Patients Pharmaceutical Preparations Preparation Prognosis Promonocyte Protein Analysis Proteins Protocols documentation RNA Receptor Protein-Tyrosine Kinases Relapse Sampling Specificity Subgroup Tail Testing Tissues Toxic effect Toxicology Ursidae Family Veins Visceromegaly Western Blotting Whole-Body Irradiation Xenograft procedure acute myeloid leukemia cell anticancer activity base benzamil beta Actin chemotherapy data integration differential expression disease phenotype experimental study improved improved outcome inhibitor leukemia lymphadenopathy monoblast monocyte mortality mouse model mutant novel nucleophosmin nucleoplasmin prognostic small molecule synergism transcriptome sequencing tumor xenograft

项目摘要

The outcomes for acute myeloid leukemia (AML) have remained poor for the past 30 years. 20- 40% of patients fail to achieve remission with induction chemotherapy, and 50-70% of patients who achieve a complete remission relapse within 3 years. A major breakthrough in dissecting out prognostic subgroups came with the discovery of the nucleophosmin (NPM1) mutation in 40%-60% of cytogenetically normal (CN)-AML cases. In subsequent analyses it has been shown that AML patients with wild-type FMS-like receptor tyrosine kinase (FLT3), bearing mutated NPM1 (NPM1mut) showed improved overall survival and relapse-free survival. We proposed that mutated NPM1 (NPM1mut) confers this advantage in AML-M5 via sequestration of FOXM1 in the cytoplasm where FOXM1 is inactive. In preliminary experiments we showed that FOXM1 inhibitors: STL427944 (C25H23N7O4) and benzamil hydrochloride (C13H15Cl2N7O) suppress nuclear FOXM1 in AML-M5 cell lines. We propose the following specific aims: Specific Aim 1. To investigate specificity of STL427944 and benzamil hydrochloride for FOXM1 suppression and their anticancer activity in AML-M5 cell lines. First, we will use monocytic AML-M5 cell lines THP1, AML-193 and U937 to confirm our preliminary data that these drugs inhibit FOXM1 in AML-M5 cell lines. Next, we will treat AML-M5 cells with STL427944 and benzamil hydrochloride and will compare FOXM1 regulatory network using RNA-seq in parental and treated cells. We will also perform ChIP-seq experiments and we will identify direct targets of FOXM1 by comparing RNA-seq and ChIP-seq experiments. Thus, as the result of data integration, we expect to have a prioritized list of functionally significant genes that belong to FOXM1 network. Specific Aim 2. To determine pharmacokinetics and efficacy of novel FOXM1 inhibitors in AML-M5 mouse models. First, we will determine toxicity, pharmacokinetics (PK) and bioavailability of STL427944 and benzamil hydrochloride. To determine toxicity of STL427944/benzamil in mice and also pharmacokinetics (PK) and bioavailability we will collaborate with the Toxicology Research Laboratory (TRL), STL427944 and benzamil will be tested in CD-1 mice. Clinical signs of toxicity and mortality will be assessed for 2 days, twice a day. To establish efficacy of STL427944/benzamil as anticancer drugs for AML-M5 in mice we will treat AML-M5 xenograft tumors with MTD of STL427944/benzamil in combination with cytarabine or venetoclax.. We will establish several groups of murine AML xenografts using different AML-M5 cell lines and will treat them with that STL427944/benzamil hydrochloride individually or in combination with cytarabine or venetoclax. The mice will be monitored for 12 weeks and disease phenotype, and life expectancy and FOXM1 levels will be compared with vehicle treated mice. These experiments will be crucial to determine whether STL427944/benzamil could be further developed as the anticancer drugs for AML-M5 patients.

过去 30 年来，急性髓系白血病 (AML) 的治疗效果仍然不佳。 20-40% 的诱导化疗未能达到缓解的患者，达到缓解的患者中有 50-70% 完全缓解3年内复发。在剖析预后亚组方面取得了重大突破在 40%-60% 细胞遗传学正常 (CN)-AML 中发现核磷蛋白 (NPM1) 突变案例。随后的分析表明，具有野生型 FMS 样受体酪氨酸的 AML 患者携带突变 NPM1 (NPM1mut) 的激酶 (FLT3) 显示出总生存期和无复发生存期的改善。我们提出，突变的 NPM1 (NPM1mut) 通过隔离 FOXM1 在 AML-M5 中赋予了这一优势。 FOXM1 失活的细胞质。在初步实验中，我们表明 FOXM1 抑制剂： STL427944 (C25H23N7O4) 和苯扎米尔盐酸盐 (C13H15Cl2N7O) 抑制 AML-M5 中的核 FOXM1 细胞系。我们提出以下具体目标：具体目标 1. 研究 STL427944 的特异性和盐酸苯扎米尔在 AML-M5 细胞系中抑制 FOXM1 及其抗癌活性。首先，我们将使用单核细胞 AML-M5 细胞系 THP1、AML-193 和 U937 来确认我们的初步数据：这些药物抑制 AML-M5 细胞系中的 FOXM1。接下来，我们将用 STL427944 处理 AML-M5 细胞，盐酸苯扎米尔，并将使用 RNA-seq 比较亲代和治疗组中的 FOXM1 调控网络细胞。我们还将进行 ChIP-seq 实验，通过比较来识别 FOXM1 的直接靶标 RNA-seq 和 ChIP-seq 实验。因此，作为数据集成的结果，我们期望有一个优先列表属于 FOXM1 网络的具有重要功能的基因。具体目标 2. 确定新型 FOXM1 抑制剂在 AML-M5 小鼠模型中的药代动力学和功效。首先，我们将确定 STL427944 和盐酸苯扎米尔的毒性、药代动力学 (PK) 和生物利用度。到确定 STL427944/benzamil 在小鼠中的毒性以及药代动力学 (PK) 和生物利用度，我们将与毒理学研究实验室（TRL）合作，STL427944和苯扎米尔将在CD-1中进行测试老鼠。将评估毒性和死亡率的临床症状，持续两天，每天两次。确定功效 STL427944/benzamil 作为小鼠 AML-M5 的抗癌药物，我们将用它来治疗 AML-M5 异种移植肿瘤 STL427944/苯扎米尔与阿糖胞苷或维奈托克联合使用的 MTD。我们将建立几组使用不同 AML-M5 细胞系的小鼠 AML 异种移植物，并将用 STL427944/benzamil 治疗它们盐酸盐单独或与阿糖胞苷或维奈托克联合使用。将监测小鼠 12 将与接受媒介物治疗的周数和疾病表型、预期寿命和 FOXM1 水平进行比较老鼠。这些实验对于确定 STL427944/benzamil 是否可以进一步开发至关重要作为 AML-M5 患者的抗癌药物。