Targeting the LIFR-LCN2 pathway to improve liver cancer therapy

靶向 LIFR-LCN2 通路改善肝癌治疗

• 批准号: 10583188
• 负责人: Li Ma
• 金额: $ 48.01万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583188
• 关键词: BAY 54-9085; Biological Markers; Breeding; CD8-Positive T-Lymphocytes; Cancer Etiology; Cell Death; Cell Survival; Clinical; Combined Modality Therapy; Cystine; Cytotoxic T-Lymphocytes; Data; Development; Down-Regulation; Drug Metabolic Detoxication; Electrons; Future; Genes; Genetic study; Genetically Engineered Mouse; Glutathione; Goals; Hepatocarcinogenesis; Hepatocyte; Homeostasis; Human; Hydroxyl Radical; Immune checkpoint inhibitor; Immunotherapy; Infiltration; Iron; Knock-out; Knockout Mice; LCN2 gene; Link; Lipid Peroxides; Liver; Liver neoplasms; Malignant neoplasm of liver; Mediating; Molecular; NR0B2 gene; Oncogenes; Organ; PD-1/PD-L1; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological Processes; Prediction of Response to Therapy; Primary carcinoma of the liver cells; Process; Production; Proliferating; Proteins; Reaction; Receptor Inhibition; Repression; Resistance; Role; Signal Transduction; Sleeping Beauty; Systemic Therapy; T cell infiltration; T-Cell Proliferation; T-Lymphocyte; TRAF6 gene; Therapeutic; Therapeutic Studies; Toxic effect; Tumor Suppressor Proteins; Ubiquitination; Unresectable; Up-Regulation; Work; anti-PD-1; anti-PD-L1; bevacizumab; cancer cell; cancer therapy; cell growth regulation; cell type; clinical development; cytokine; derepression; glutathione peroxidase; immune cell infiltrate; immune checkpoint; improved; in vivo; insight; iron deficiency; leukemia inhibitory factor receptor; liver cancer model; mortality; neoplastic cell; neutralizing antibody; novel drug combination; overexpression; patient derived xenograft model; patient subsets; predicting response; predictive marker; receptor binding; receptor expression; receptor function; role model; targeted cancer therapy; therapeutic target; timeline; treatment response; tumor; tumor progression

PROJECT SUMMARY/ABSTRACT Iron is vital for many physiological processes, but excessive iron causes toxicity. Dysregulated iron homeostasis (either iron deficiency or overload) is a harbinger of pathological conditions. The liver stores iron in hepatocytes and is the major organ that controls systemic iron homeostasis. Liver cancer, primarily hepatocellular carcinoma (HCC), is highly lethal with limited treatment options and no biomarkers to predict therapy response. Leukemia inhibitory factor receptor (LIFR) is frequently downregulated in human HCC; however, in vivo and genetic studies of LIFR’s functions in liver cancer development and therapy response were lacking. Recently, by constructing and characterizing hepatocyte-specific and inducible Lifr-knockout mice, we found that loss of Lifr promoted liver tumorigenesis and conferred resistance to sorafenib-induced ferroptosis, a non-apoptotic type of cell death characterized by the iron-dependent accumulation of lipid hydroperoxides. Our data also pointed to a role for LIFR in inhibiting NF-κB signaling in the liver, which in turn downregulates lipocalin 2 (LCN2), an iron- sequestering cytokine. In parallel, our data revealed that in oncogene-induced liver tumors, overexpression of LIFR increased, while knockout of Lifr decreased CD8+ T cell infiltration, which may be mediated by LCN2- dependent downregulation of iron levels, viability, and proliferation of T cells. Altogether, these data support a hypothesis that loss or downregulation of LIFR in liver cancer leads to upregulation of LCN2, which on one hand confers resistance to ferroptosis on liver tumor cells, and on the other hand, deprives T cells of iron that is essential for T cell viability, proliferation, and effector function; both mechanisms contribute to liver cancer progression and therapy resistance. In the proposed work, we will elucidate the molecular mechanisms by which LIFR inhibits NF-κB signaling in liver cells (Specific Aim 1). Further, we will investigate whether LCN2 can serve as a therapeutic target for enhancing sorafenib efficacy in HCC (Specific Aim 2). Finally, we will study whether LIFR or therapeutic LCN2 neutralization can sensitize HCC to immunotherapy (Specific Aim 3). Genetically engineered mouse models, Sleeping Beauty transposon-mediated oncogene-induced liver cancer models, and HCC patient-derived xenograft models will be used to study the therapeutic potential and mechanisms of action of two novel drug combinations, which will illuminate how to improve liver cancer therapy by targeting an iron- sequestering pathway. We envision that low LIFR expression and high LCN2 expression could be used to select HCC patients who will likely benefit from the combination therapy with the LCN2-neutralizing antibody plus sorafenib or immune checkpoint inhibitors.

项目摘要/摘要 铁对于许多物理过程至关重要，但是铁过多会引起毒性。铁稳态失调 （铁缺乏或过载）是病理状况的预兆。肝细胞中的铁储存 并且是控制全身铁稳态的主要器官。肝癌，原发性肝细胞癌 （HCC）具有高度致命的治疗选择，没有生物标志物来预测治疗反应。白血病 抑制因子受体（LIFR）经常在人类HCC中下调；但是，体内和遗传研究 缺乏LIFR在肝癌开发和治疗反应中的功能。最近，通过构造 并表征肝细胞特异性和诱导型LIFR-敲除小鼠，我们发现LIFR的损失促进了肝脏 肿瘤发生和对索拉非尼诱导的铁凋亡的抗性，这是一种非凋亡类型的细胞死亡 以脂质氢过氧化物的铁依赖性积累为特征。我们的数据还指出了 LIFR在抑制肝脏中的NF-κB信号传导中，进而下调Lipocalin 2（LCN2），铁 - 隔离细胞因子。同时，我们的数据表明，在癌基因诱导的肝肿瘤中，过表达 LIFR增加，而LIFR的敲除CD8+ T细胞浸润降低，这可能是由LCN2-介导的 铁水平，活力和T细胞增殖的依赖下调。这些数据完全支持 假设肝癌中LIFR的丧失或下调导致LCN2的上调，这一方面 赋予对肝肿瘤细胞上的铁毒性的抗性，另一方面，剥夺了T细胞的铁 对于T细胞活力，增殖和效应子功能所必需的；两种机制都导致肝癌 进展和抗治疗性。在拟议的工作中，我们将阐明分子机制 LIFR抑制肝细胞中的NF-κB信号传导（特定目标1）。此外，我们将调查LCN2是否可以服务 作为提高索拉非尼在HCC中效率的治疗靶标（特定目标2）。最后，我们将研究是否 LIFR或治疗性LCN2神经化可以将HCC感知到免疫疗法（特定目标3）。遗传 工程的小鼠模型，睡美人转座子介导的癌基因诱导的肝癌模型， HCC患者衍生的Xenograpony模型将用于研究作用的治疗潜力和机制 在两种新型药物组合中，这将通过靶向铁来阐明如何改善肝癌治疗 隔离途径。我们设想低LIFR表达和高LCN2表达可用于选择 HCC患者可能会从与LCN2中和抗体加的联合疗法中受益 索拉非尼或免疫切除点抑制剂。