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.

抽象的急性髓系白血病 (AML) 的特点是分化阻断和髓系前体细胞的克隆增殖尽管进行了大量的研究工作，但最终导致正常造血功能衰竭的细胞却很少有治疗方法。过去 40 年来取得了进步，但绝大多数患者的死亡率仍然很高抗凋亡蛋白 BCL-2 的过度表达是治疗后五年内患病的标志之一。 AML。一类新的小分子抑制剂，称为 BH3 模拟物，选择性靶向特定的 BCL-2 家族。 Venetoclax (VEN) 是一种选择性 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，显示出反应尽管取得了这些显着的成果，但原发性和获得性 VEN 耐药性仍然是我们所关注的问题。其他人表明，VEN 抵抗主要是通过另一个 BCL-2 家族成员的上调而发生的，诱导骨髓性白血病细胞分化蛋白 (MCL-1)，抑制 MCL-1 会导致 VEN 耐药细胞凋亡。然而，在对这些基础进行进一步分析后，我们观察到 BH3 模拟物的反应不一致。 primagraft AML PDX 模型的不同造血室 BH3 分析和 AML primagraft PDX 骨。使用骨髓单核细胞进行的骨髓扩张研究可以准确预测患者特定的 BH3 依赖性，但是尽管外周细胞通常具有相同的克隆性和特征，但我们在外周血中看到了相互矛盾的结果。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 更敏感无论骨髓 BH3 依赖性如何，细胞系和患者来源的异种移植物均受到抑制。准确地说，AML 中的外周母细胞比骨髓中的母细胞对 MCL-1 抑制更敏感，并且提出使用动员剂将增加 AML 细胞对 MCL-1 抑制的敏感性，可能减少我们将利用我们实验室的宝贵资源和实现缓解所需的 MCL-1 抑制剂剂量。检验这一假设的专业知识具有以下目的： 1. 评估 AML 母细胞的 BH3 依赖性特征从患者的骨髓和外周以及 PDX 模型中采集，2. 确定动员的效用：增强BH3模拟物的辅助疗法这些研究将进一步阐明BCL-2家族之间的关系。母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此外，众所周知，骨髓生态位提供了增殖和生存优势。在化疗耐药中，CXCR4 激动剂 Plerixafor 已成功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缓疾病复发。重要的是，由于 BH3 模拟物并非没有毒性，这些研究将调查普乐沙福增强对基于 BH3 模拟的治疗方案有反应，或减少在 VEN 初治和 VEN 中实现反应所需的剂量耐药性 AML。