Targeting Galectin-1 with radiation in lung cancer

用放射疗法靶向 Galectin-1 治疗肺癌

• 批准号: 8446983
• 负责人: ALBERT KOONG
• 金额: $ 30.72万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8446983
• 关键词: Address; Adhesions; Adverse effects; Affect; Apoptosis; Apoptotic; Behavior; Binding; Biological; Blocking Antibodies; Cancer Patient; Cancer cell line; Carbohydrates; Cell Death; Cell Hypoxia; Cell Surface Proteins; Cell physiology; Cells; Cisplatin; Clinic; Clinical; Conformal Radiotherapy; Data; Disaccharides; Disease; Dose; Drops; Effectiveness; Failure; Family; Future; Galactose; Galectin 1; Genes; Goals; Homeostasis; Human; Hypoxia; Immune; Immune system; Implant; In Vitro; Knock-out; Lectin; Ligands; Lymphopenia; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mus; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Pathologic Processes; Pathway interactions; Patients; Peripheral; Plasma; Play; Principal Investigator; Process; Protein Binding; Proteins; Proteomics; RNA Splicing; Radiation; Radiation therapy; Recombinants; Reporting; Repression; Research Personnel; Role; Solid; Solid Neoplasm; T-Cell Depletion; T-Lymphocyte; Time; Toxic effect; Treatment outcome; Tumor Immunity; Tumor Oxygenation; Tumor-Derived; Wild Type Mouse; angiogenesis; base; cancer cell; carbohydrate binding protein; cell killing; chemotherapy; design; improved; in vivo; member; migration; neoplastic cell; novel; novel strategies; research study; response; small hairpin RNA; success; tumor; tumor growth; tumor progression; Address; Adhesions; Adverse effects; Affect; Apoptosis; Apoptotic; Behavior; Binding; Biological; Blocking Antibodies; Cancer Patient; Cancer cell line; Carbohydrates; Cell Death; Cell Hypoxia; Cell Surface Proteins; Cell physiology; Cells; Cisplatin; Clinic; Clinical; Conformal Radiotherapy; Data; Disaccharides; Disease; Dose; Drops; Effectiveness; Failure; Family; Future; Galactose; Galectin 1; Genes; Goals; Homeostasis; Human; Hypoxia; Immune; Immune system; Implant; In Vitro; Knock-out; Lectin; Ligands; Lymphopenia; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mus; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Pathologic Processes; Pathway interactions; Patients; Peripheral; Plasma; Play; Principal Investigator; Process; Protein Binding; Proteins; Proteomics; RNA Splicing; Radiation; Radiation therapy; Recombinants; Reporting; Repression; Research Personnel; Role; Solid; Solid Neoplasm; T-Cell Depletion; T-Lymphocyte; Time; Toxic effect; Treatment outcome; Tumor Immunity; Tumor Oxygenation; Tumor-Derived; Wild Type Mouse; angiogenesis; base; cancer cell; carbohydrate binding protein; cell killing; chemotherapy; design; improved; in vivo; member; migration; neoplastic cell; novel; novel strategies; research study; response; small hairpin RNA; success; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Non-small cell lung cancer (NSCLC) is a highly lethal disease. Despite dose escalation with conformal radiotherapy (RT), there is still a high intrathoracic failure rate. A novel approach is needed to improve RT effectiveness in these tumors. Galectin-1 (Gal-1) is a secreted carbohydrate binding lectin that is well known for its rol in modulating T cell homeostasis. More recently, it has been shown to play a major role in cancer progression. It is expressed in many cancers, including NSCLC, and its expression has been correlated with aggressive tumor behaviors. Gal-1 has been implicated in several pathologic processes including tumor proliferation, aggregation, adhesion, migration, angiogenesis and enhancing T-cell apoptosis, which can, in turn, can confer tumor immunity. Using proteomic analysis, we found that Gal-1 secretion was enhanced by hypoxia and more recently by RT. Applying a combination of down-regulating Gal-1 in a non-NSCLC cell line and knocking-out the gene in host mice, we show that tumor-derived Gal-1 is more important than host- derived Gal-1 in promoting tumor growth and spontaneous metastasis (Appendix 3). Further mechanistic studies suggested that Gal-1 mediated its tumor promoting function by protecting hypoxic tumor cells from apoptosis while enhancing intratumoral T-cell death. We also found that Gal-1 is required for XPB1 splicing, a regulator of the unfolded protein (UPR) pathway. The UPR is a well-known pro-survival pathway reported by several investigators to protect cancer cells from hypoxia-induced cell death. Based on these data, it is logical to ask the following questions: (1) does the Ire1/XBP1 pathway mediate Gal-1 induced tumor cell apoptosis and (2) does targeting Gal-1 with RT and chemotherapy increase tumor control in hypoxic NSCLC? A major goal of this study is to understand the pro-survival function the Gal-1 in hypoxic tumor cells and to determine whether targeting this protein will increase RT efficacy in hypoxic NSCLC. A common clinical observation is that RT can often cause profound lymphopenia in cancer patients & the exact mechanism for such an effect is unknown. We hypothesize that RT induces Gal-1 secretion, which in turn causes global T-cell apoptosis, resulting in lymphopenia. A secondary goal of this proposal is to study the role of Gal-1 in RT-mediated lymphopenia and to determine whether blocking Gal-1 will ameliorate this affect. We will address the above stated goals using 3 specific aims. In Aim 1, we will evaluate the role of Ire1- XBP1 pathway in Gal-1 mediated tumor cell apoptosis under hypoxia and determine whether XBP1 activation is sufficient and required for this process. In Aim 2, we will determine whether repression of Gal-1 expression or inhibiting its function (blocking antibody or inhibitory disaccharide) will enhance RT and cisplatin chemotherapy effect in NSCLC cell lines and orthotopic mouse tumors. In addition, we will determine whether this effect is dependent on tumor oxygenation and on having an intact T-cell function in mice using T-cell depletion experiments. Finally, in Aim 3, we will establish whether Gal-1 tumor or host expression is required and necessary for RT-induced lymphopenia using a combination of genetically matched Gal-1 deficient tumors and Gal-1 deficient host. We will also correlate circulating Gal-1 level with peripheral T-lymphocyte levels in patients undergoing RT for solid cancers. These studies will help to establish that Gal-1 is a novel target that can be used in conjunction with RT to improve the treatment outcome in NSCLC.

描述（由申请人提供）：非小细胞肺癌（NSCLC）是一种高度致命的疾病。尽管剂量升级，同型放射疗法（RT）仍然存在较高的胸腔内衰竭率。需要一种新的方法来提高这些肿瘤中的RT效率。 Galectin-1（Gal-1）是一种分泌的碳水化合物结合凝集素，以调节T细胞稳态的ROL而闻名。最近，它已显示出在癌症进展中起主要作用。它在包括NSCLC在内的许多癌症中表达，其表达与侵袭性肿瘤行为相关。 GAL-1与多种病理过程有关，包括肿瘤增殖，聚集，粘附，迁移，血管生成和增强T细胞凋亡，这可以赋予肿瘤免疫力。使用蛋白质组学分析，我们发现缺氧增强了GAL-1分泌，而最近由RT增强了GAL-1分泌。在非NSCLC细胞系中使用下调的GAL-1组合并在宿主小鼠中淘汰基因，我们表明肿瘤衍生的GAL-1在促进肿瘤生长和自发转移方面比宿主衍生的GAL-1更重要（附录3）。进一步的机械研究表明，GAL-1通过保护低氧肿瘤细胞免受凋亡的同时增强肿瘤内T细胞死亡而介导了其肿瘤促进功能。我们还发现，XPB1剪接是所需的GAL-1，这是展开蛋白（UPR）途径的调节剂。 UPR是几位研究人员报告的众所周知的促生途径，以保护癌细胞免受缺氧诱导的细胞死亡的影响。基于这些数据，询问 以下问题：（1）IRE1/XBP1途径是否介导GAL-1诱导肿瘤细胞凋亡，并且（2）（2）将GAL-1靶向RT和化学疗法会增加缺氧NSCLC中的肿瘤控制吗？这项研究的主要目的是了解缺氧性肿瘤细胞中的促生物性功能GAL-1，并确定靶向该蛋白质是否会提高低氧NSCLC中的RT疗效。 一个常见的临床观察结果是，RT通常会在癌症患者中引起严重的淋巴细胞减少症，并且这种作用的确切机制尚不清楚。我们假设RT诱导GAL-1分泌，这又导致全球T细胞凋亡，导致淋巴细胞减少。该提案的次要目标是研究GAL-1在RT介导的淋巴细胞减少症中的作用，并确定阻止GAL-1是否会改善这种影响。 我们将使用3个特定目标来解决上述既定目标。在AIM 1中，我们将评估IRE1-XBP1途径在gal-1介导的缺氧下介导的肿瘤细胞凋亡中的作用，并确定XBP1激活是否足够且需要该过程。在AIM 2中，我们将确定GAL-1表达的抑制或抑制其功能（阻断抗体或抑制性二糖）是否会增强NSCLC细胞系和原位小鼠肿瘤中的RT和顺铂化学疗法。此外，我们将确定这种作用是否取决于肿瘤的氧合和使用T细胞耗竭实验在小鼠中具有完整的T细胞功能。最后，在AIM 3中，我们将使用遗传匹配的GAL-1缺陷肿瘤和GAL-1缺乏宿主的组合来确定RT诱导的淋巴细胞减少症是否需要GAL-1肿瘤或宿主表达。我们还将在接受RT的固体癌症患者中将循环GAL-1水平与周围的T淋巴细胞水平相关联。这些研究将有助于确定GAL-1是一个可以与RT结合使用的新目标 改善NSCLC的治疗结果。