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

项目摘要/摘要 急性髓系白血病(AML)，一种迅速致命的疾病，其特征是恶性细胞的不受控制的增殖 血液和骨髓中的细胞，是成人最常见的急性白血病。五年存活率 仍然很穷(23.4%)，65岁以上的人急剧下降到5%。预后尤其令人沮丧 顽固性疾病患者或在首次治疗一年内复发的患者。护理的标准 在这种情况下，大剂量化疗的疗效有限，发病率高。因此，这是一个具有 未得到满足的紧急临床需求。先前的研究表明，肝细胞生长因子(HGF)/c-Met 轴心对白血病细胞的存活很重要。基于这一发现，我们进行了一项I期临床试验 用抗肝细胞生长因子的单抗联合化疗。这项研究已经产生了临床应用 回复率约为55%，而使用类似资格标准的历史回复率仅为20%-25% 和化疗的脊梁。使用预期收集的高维、单细胞分析 外周血单个核细胞，P-S6的减弱被认为是反应的生物标志物和促进 炎症、I型干扰素(干扰素)特征和持续升高的HGF是不良预后指标。 有无c-met处理的AML细胞的差异基因表达谱 抑制剂Crizotinib提示HGF在临床无反应者中的表达升高可能是由 BCL6辅阻遏子蛋白(BCOR)，多梳复合体的成员。我们建议的研究将 利用前瞻性收集的患者样本与这项临床试验的注释结果相关联，这是一项新的临床试验 空间分布技术和临床前遗传模型1)研究BCOR的功能后果 肝细胞生长因子表达缺失与急性髓系白血病的体内发展，2)检测联合治疗的疗效 表观遗传调节剂与非那曲坦单抗联合治疗AML并阐明这种联合治疗对全球 染色质状态与肿瘤免疫微环境。这项研究产生的结果将为 为未来临床反应和疾病监测的患者分层发现生物标记物。这项工作可能会 也提名潜在的合理的联合疗法来改善患者对HGF抗体的应答 具有从头耐药，从而改善急性髓系白血病患者的生活质量和总体生存。

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.