Targeting Autocrine Hepatocyte Growth Factor (HGF) Production as a Therapeutic Modality in Acute Myeloid Leukemia (AML)

靶向自分泌肝细胞生长因子 (HGF) 的产生作为急性髓系白血病 (AML) 的治疗方式

• 批准号: 10589002
• 负责人: Bradley Wayne Blaser
• 金额: $ 23.81万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-08 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10589002
• 关键词: 3-Dimensional; Acceleration; Acute Myelocytic Leukemia; Acute leukemia; Adult; Animals; Anthracycline; Antibodies; Area; BCL1 Oncogene; BCL6 gene; Bioinformatics; Biology; Blood; Bone Marrow; Cell Line; Chromatin; Clinical; Clinical Trials; Clinical stratification; Combined Modality Therapy; Complex; Cytarabine; Cytometry; Cytotoxic Chemotherapy; Data; Development; Disease; Dose; Down-Regulation; Drops; Drug resistance; EZH2 gene; Eligibility Determination; Epigenetic Process; Future; Gene Expression Profiling; Genetic; Genetic Models; Genetically Engineered Mouse; Growth Factor Inhibition; HGF gene; Hematopoiesis; High Dose Chemotherapy; Immune; Immunotherapy; In Vitro; Inflammatory; Interferon Type I; Interferons; Intervention; Link; Mediating; Modality; Modeling; Molecular; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Mus; Mutation; Myelogenous; Outcome; Pathway interactions; Patient Selection; Patients; Peripheral Blood Mononuclear Cell; Phase; Phase I Clinical Trials; Phase Ib Clinical Trial; Polycomb; Pre-Clinical Model; Principal Investigator; Production; Prognosis; Proliferating; Proteins; Publishing; Quality of life; Recurrent disease; Refractory; Refractory Disease; Regimen; Regulation; Relapse; Reporting; Research; Resistance; Safety; Sampling; Specimen; Survival Rate; System; Technology; Testing; Therapeutic; Tissue-Specific Gene Expression; Toxic effect; Treatment Efficacy; Tumor-associated macrophages; United States; Up-Regulation; Vertebral column; Work; Zebrafish; acute myeloid leukemia cell; antitumor effect; attenuation; autocrine; biomarker discovery; biomarker identification; cancer cell; chemotherapy; clinical development; crizotinib; cytokine; experience; first-in-human; genetic corepressor; high dimensionality; high throughput screening; human old age (65+); immune cell infiltrate; improved; in vivo; inhibitor; innovation; leukemia; leukemogenesis; loss of function mutation; member; mortality; novel; novel therapeutics; paracrine; patient stratification; pre-clinical; predicting response; predictive marker; prognostic indicator; programmed cell death ligand 1; prospective; resistance mechanism; response; response biomarker; single cell analysis; single-cell RNA sequencing; standard of care; targeted agent; therapeutic evaluation; tumor; tumor microenvironment; tumor-immune system interactions

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML), a rapidly fatal disease characterized by uncontrolled proliferation of malignant cells in the blood and the bone marrow, is the most common acute leukemia in adults. The 5-year survival rate remains poor (23.4%) and drops precipitously to 5% for those over age 65. Prognosis is particularly dismal for patients with refractory disease or those who relapsed within one year of initial treatment. The standard of care high dose chemotherapy has limited efficacy and high morbidity in this setting. Thus, this is an area with an urgent unmet clinical need. Prior research has demonstrated that the hepatocyte growth factor (HGF)/c-MET axis to be important for leukemia blasts survival. Based on this finding, we conducted a phase I clinical trial using a monoclonal antibody against HGF combined with chemotherapy. This study has produced clinical responses of ~ 55%, compared with historical response rates of only 20-25% using similar eligibility criteria and chemotherapy backbone. Using high-dimensional, single-cell analyses of prospectively-collected peripheral blood mononuclear cells, attenuation of p-S6 was identified as a biomarker of response and a pro- inflammatory, type I interferon (IFN) signature and persistently elevated HGF as adverse prognostic indicators. Differential gene expression profiling between AML cells treated in the presence and absence of the c-MET inhibitor crizotinib suggests that the elevated HGF expression in the clinical non-responders may be mediated by the BCL6 corepressor protein (BCOR), a member of the Polycomb complex. Our proposed study will leverage prospectively-collected patients samples linked to annotated outcomes from this clinical trial, a novel spatial profiling technology, and preclinical genetic models 1) to study the functional consequence of BCOR loss on HGF expression and AML development in vivo, 2) to test the therapeutic efficacy of combining epigenetic modulators with ficlatuzumab to treat AML and elucidate the effect of this combination on the global chromatin state and the tumor immune microenvironment. Results generated from this study will inform biomarker discovery for future patient stratification of clinical response and disease monitoring. This work may also nominate potential rationale combination therapies to improve responses to the HGF antibody for patients with de novo resistance, thus improving quality of life and overall survival for patients with AML.

项目摘要/摘要 急性髓样白血病（AML），一种迅速致命的疾病，其特征是恶性增生 血液和骨髓中的细胞是成人最常见的急性白血病。 5年生存率 在65岁以上的人中仍然很差（23.4％），并急剧下降至5％。预后尤其令人沮丧 难治性疾病或初次治疗后一年内复发的患者。护理标准 在这种情况下，高剂量化疗的功效有限，发病率高。因此，这是一个有一个 紧急未满足的临床需求。先前的研究表明，肝细胞生长因子（HGF）/C-MET 轴对白血病爆炸至关重要。基于这一发现，我们进行了I期临床试验 使用针对HGF的单克隆抗体与化学疗法结合。这项研究产生了临床 使用类似的资格标准，与仅20-25％的历史响应率相比，响应约为55％ 和化学疗法骨干。使用前瞻性收集的高维单细胞分析 外周血单核细胞，p-S6的衰减被确定为反应的生物标志物，并且 炎症，I型干扰素（IFN）签名，并持续升高HGF作为不良预后指标。 在存在和不存在C-MET的情况下处理的AML细胞之间的差异基因表达分析 抑制剂crizotinib表明临床非反应器中的HGF表达升高可能是介导的 由polycomb复合物的成员Bcl6 Corepressor蛋白（BCOR）。我们提出的研究将 利用前瞻性收集的患者样品与该临床试验的注释结果相关的样本，这是一种新型 空间分析技术和临床前遗传模型1）研究BCOR的功能后果 HGF表达和体内AML发育的损失，2）测试组合的治疗功效 具有ficlatuzumab的表观遗传调节剂，以治疗AML并阐明该组合对全局的影响 染色质状态和肿瘤免疫微环境。这项研究产生的结果将告知 生物标志物发现用于未来的患者临床反应和疾病监测的分层。这项工作可能 还提名了潜在的基本原理组合疗法，以改善患者对HGF抗体的反应 具有从头耐药性，从而改善了AML患者的生活质量和整体生存率。