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Effects of microenvironmental modulation on BH3 dependence in AML

微环境调节对 AML 中 BH3 依赖的影响

基本信息

批准号：
10047037
负责人：
Haley Elizabeth Ramsey
金额：
$ 17.3万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-09 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10047037
关键词：
AMD3100 Acute Myelocytic Leukemia Affect Aftercare Agonist Apoptosis Apoptotic BCL2 gene Biological Assay Blast Cell Blood Blood Circulation Bone Marrow CXCR4 gene Cell Differentiation process Cell Line Cells Characteristics Clonal Expansion Clonality DNA Methyltransferase Inhibitor Data Dependence Disease Dose Elderly Acute Myeloblastic Leukemia Exhibits Exposure to FDA approved Failure Family member Growth Harvest Hematopoiesis Hematopoietic Ineffective Hematopoiesis Inhibitor of Differentiation Proteins Laboratories Marrow Measures Modeling Monitor Mononuclear Mus Myelogenous Myeloid Cells Patients Peripheral Pharmaceutical Preparations Population Protein Family Protein Inhibition Protein Overexpression Proteins Recurrent disease Regimen Relapse Research Residual state Resistance Resistance development Resources Sampling Stream Testing Therapeutic Time Toxic effect Tumor Burden Up-Regulation Work Xenograft Model Xenograft procedure acute myeloid leukemia cell base bone cell bone marrow xenograft cancer cell chemotherapy clinical care clinical investigation comparative efficacy cytochrome c cytopenia in vivo inhibitor/antagonist leukemic stem cell mimetics mortality myeloid leukemia cell overexpression patient response peripheral blood precursor cell protein expression response small molecule inhibitor standard of care success

项目摘要

Abstract Acute Myeloid Leukemia (AML) is characterized by differentiation blockade and the clonal proliferation of myeloid precursor cells that culminates in the failure of normal hematopoiesis. Regardless of intensive research efforts, few therapeutic advancements have been made in past 40 years, and mortality remains high with the overwhelming majority of patients succumbing to disease within five years of treatment. Overexpression of anti-apoptotic protein, BCL-2, is one hallmark of AML. A new class of small molecule inhibitors, referred to as BH3 mimetics, selectively target specific BCL-2 family proteins. Venetoclax (VEN), a selective BCL-2 inhibitor, was recently approved by the FDA in combination with DNA methyltransferase inhibitors for use in elderly AML patients unfit to receive standard chemotherapy, exhibiting response rates up to 70%. Despite these remarkable results, primary and acquired VEN resistance remains a concern. We and others have shown that VEN resistance occurs mainly through the upregulation of another BCL-2 family member, induced myeloid leukemia cell differentiation protein (MCL-1), and that inhibition of MCL-1 leads to apoptosis in VEN resistant cells. However, upon further analyses of these underpinnings, we observed discordance in response to BH3 mimetics in the different hematopoietic compartments of primagraft AML PDX models. BH3 profiling and AML primagraft PDX bone marrow expansion studies using bone marrow mononuclear cells accurately predict patient specific BH3 dependency, but we have seen contradictory results in the peripheral blood. Although peripheral cells are often of the same clonality and differentiation stage as in the bone marrow, our studies indicate that peripheral AML blasts are more sensitive to MCL-1 inhibition in both cell line and patient derived xenografts, regardless of marrow BH3 dependency. Therefore, we hypothesize that peripheral blast cells in AML are more sensitive to MCL-1 inhibition than those in the bone marrow and propose that the use of mobilization agents will increase sensitivity of AML cells to MCL-1 inhibition, potentially reducing the dose of MCL-1 inhibitors needed to achieve response. We will leverage our laboratory’s invaluable resources and expertise to test this hypothesis with the following aims: 1. Assess the BH3 dependent characteristics of AML blasts harvested from the bone marrow and periphery of patients and PDX models and 2. Determine the utility of mobilization as an accessory therapy to enhance BH3 mimetics. These studies will further elucidate the relationship between BCL-2 family proteins in blast cells and different hematopoietic microenvironments and whether altering the microenvironment can affect this relationship. Further, as it is well known that the marrow niche provides proliferative and survival advantages that result in chemotherapy resistance, plerixafor, a CXCR4 agonist, has successfully been used in combination with other agents in AML as a mobilization agent to release cells from the bone marrow into the periphery and delay disease relapse. Importantly, as BH3 mimetics are not without toxicity, these studies will investigate the utility of plerixafor to enhance response to BH3 mimetic based regimens or reduce the dose needed to achieve response in both VEN naïve and VEN resistant AML.

摘要急性髓系白血病（AML）以分化阻滞和髓系前体细胞克隆性增殖为特征导致正常造血功能衰竭的细胞。尽管进行了大量的研究，在过去的40年里取得了进步，但绝大多数患者的死亡率仍然很高，在接受治疗的五年内死于疾病。抗凋亡蛋白BCL-2的过表达是肿瘤细胞凋亡的标志之一。急性髓细胞白血病一类新的小分子抑制剂，称为BH 3模拟物，选择性靶向特定的BCL-2家族 proteins.维奈托克（VEN），一种选择性BCL-2抑制剂，最近被FDA批准与DNA联合使用。甲基转移酶抑制剂用于不适合接受标准化疗的老年AML患者，显示出反应率高达70%。尽管有这些显著的结果，原发性和获得性VEN耐药仍然是一个问题。我们和其他人已经表明VEN抗性主要通过另一个BCL-2家族成员的上调而发生，髓样白血病细胞分化蛋白（MCL-1），并且MCL-1的抑制导致VEN抗性细胞中的细胞凋亡。然而，在进一步分析这些基础后，我们观察到在小鼠中对BH 3模拟物的反应不一致。 Primagraft AML PDX模型的不同造血区室。BH 3谱分析和AML primagraft PDX骨使用骨髓单核细胞的骨髓扩增研究准确预测了患者特异性BH 3依赖性，但我们在外周血中看到了相互矛盾的结果。虽然外周细胞通常具有相同的克隆性，与骨髓中的分化阶段一样，我们的研究表明外周AML母细胞对MCL-1更敏感，在细胞系和患者来源的异种移植物中的抑制，而不管骨髓BH 3依赖性。所以我们假设AML中的外周母细胞比骨髓中的母细胞对MCL-1抑制更敏感，提出使用动员剂将增加AML细胞对MCL-1抑制的敏感性，潜在地减少AML细胞的增殖。达到反应所需的MCL-1抑制剂剂量。我们将利用实验室的宝贵资源，专业知识来测试这一假设与以下目标：1。评估AML原始细胞的BH 3依赖性特征从患者和PDX模型的骨髓和外周收获;确定动员的效用，增强BH 3模拟物的辅助疗法。这些研究将进一步阐明BCL-2家族与细胞凋亡的关系。原始细胞和不同造血微环境中的蛋白质，以及改变微环境是否会影响这种关系此外，众所周知，骨髓龛提供增殖和存活优势，在化疗耐药性中，普乐沙福（一种CXCR 4激动剂）已成功地与其他药物联合使用， AML作为动员剂将细胞从骨髓释放到外周并延迟疾病复发。重要的是，由于BH 3模拟物并非没有毒性，这些研究将研究普乐沙福在增强对基于BH 3模拟物的方案的反应或减少VEN初治和VEN中达到反应所需的剂量耐药AML。