Effects of microenvironmental modulation on BH3 dependence in AML

微环境调节对 AML 中 BH3 依赖的影响

• 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
• 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

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 急性髓样白血病（AML）的特征是分化阻滞和髓样前体的克隆增殖 最终导致正常造血作用的细胞。不管密集的研究工作如何，很少有治疗性 在过去的40年中，进步已经取得进步，而大多数患者的死亡率仍然很高 在治疗五年内屈服于疾病。抗凋亡蛋白的过表达Bcl-2是 AML。一种新的小分子抑制剂，称为BH3 Mimetics，有选择地靶向特定的Bcl-2家族 蛋白质。 Venetoclax（VEN）是一种选择性Bcl-2抑制剂，最近被FDA与DNA结合使用 甲基转移酶抑制剂用于古老的AML患者不适合接受标准化疗，表现出反应 利率高达70％。尽管有这些显着的结果，但主要和获得的VEN阻力仍然是一个令人担忧的问题。我们和 其他人则表明，抗电阻主要是通过另一个Bcl-2家庭成员的上调发生的 髓样白血病细胞分化蛋白（MCL-1），并且对MCL-1的抑制会导致抗VEN耐药细胞的细胞凋亡。 但是，在对这些基础的进一步分析后，我们观察到对BH3模拟物的不一致性 Primagraft AML PDX模型的不同造血室。 BH3分析和AML Primagraft PDX骨骼 使用骨髓单核细胞的骨髓扩展研究准确预测患者特定的BH3依赖性，但 我们已经看到外周血矛盾的结果。尽管外围细胞通常具有相同的克隆性，并且 分化阶段与骨髓一样，我们的研究表明外周AML爆炸对MCL-1更敏感 细胞系和患者衍生的异种移植物的抑制作用，无论骨髓BH3依赖性如何。因此，我们 假设AML中的外周爆炸细胞对MCL-1的抑制更敏感 提议使用动员剂将增加AML细胞对MCL-1抑制的敏感性，并有可能降低 MCL-1抑制剂的剂量需要实现反应。我们将利用实验室的宝贵资源和 以下目的测试该假设的专业知识：1。评估AML爆炸的BH3依赖性特征 从患者和PDX模型的骨髓和外围收获和2。 可增强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 爆炸细胞中的蛋白质和不同的造血微环境以及改变微环境是否会影响 这种关系。此外，众所周知，骨髓的利基市场提供了产生的增殖和生存优势 在化学疗法抗性中，CXCR4激动剂Plerixafor已成功地与其他药物结合使用 AML作为动员剂，将细胞从骨髓释放到周围和延迟疾病释放。 重要的是，由于BH3 Mimetics并非没有毒性，因此这些研究将研究Plerixafor的实用性 对基于BH3的基于BH3的反应或减少在幼稚和VEN中达到反应所需的剂量 抗性AML。