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.

项目总结/摘要 急性髓性白血病（AML）是一种快速致死性疾病，其特征是恶性淋巴细胞不受控制的增殖， 白血病是一种急性白血病，它是血液和骨髓中最常见的白血病。5年生存率 仍然贫穷（23.4%），65岁以上的人急剧下降到5%。预后尤其令人沮丧， 难治性疾病患者或在初始治疗后一年内复发的患者。护理标准 高剂量化疗在这种情况下疗效有限且发病率高。因此，这是一个 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 轴对白血病原始细胞存活很重要。基于这一发现，我们进行了一期临床试验， 使用抗HGF的单克隆抗体联合化疗。这项研究产生了临床 缓解率约为55%，而使用类似的合格性标准，历史缓解率仅为20-25% 和化疗骨干。使用高维，单细胞分析前瞻性收集的 外周血单个核细胞，p-S6的衰减被确定为反应的生物标志物， 炎症、I型干扰素（IFN）特征和持续升高的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谱 抑制剂克唑替尼表明，临床无应答者中HGF表达升高可能是由 BCL 6辅阻遏蛋白（BCOR），Polycomb复合体的一员。我们建议的研究将 利用前瞻性收集的患者样本与本临床试验的注释结果相关， 空间分析技术和临床前遗传模型1）研究BCOR的功能后果 HGF表达的丧失和体内AML的发展，2）测试组合 表观遗传调节剂与ficlatuzumab治疗AML并阐明这种组合对整体AML的影响 染色质状态和肿瘤免疫微环境。本研究产生的结果将告知 生物标志物发现，用于未来患者临床反应分层和疾病监测。这项工作可能 还提名了潜在的合理联合疗法，以改善患者对HGF抗体的反应， 与从头耐药，从而提高生活质量和总生存期的AML患者。