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

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(申请人提供)：非小细胞肺癌(NSCLC)是一种高度致命的疾病。尽管适形放射治疗(RT)的剂量增加，但胸腔内失败率仍然很高。需要一种新的方法来提高这些肿瘤的放射治疗效果。半乳糖凝集素-1(Galectin-1，Gal-1)是一种分泌型碳水化合物结合凝集素，以其在调节T细胞内稳态中的作用而闻名。最近，它被证明在癌症进展中发挥了重要作用。它在包括NSCLC在内的许多肿瘤中都有表达，并且它的表达与肿瘤的侵袭性行为有关。GAL-1参与了多种病理过程，包括肿瘤的增殖、聚集、黏附、迁移、血管生成和促进T细胞的凋亡，而T细胞的凋亡又可以增强肿瘤的免疫功能。利用蛋白质组学分析，我们发现Gal-1的分泌在低氧和最近被RT增强。应用在非NSCLC细胞系中下调Gal-1和在宿主小鼠中敲除该基因的组合，我们表明肿瘤来源的Gal-1在促进肿瘤生长和自发转移方面比宿主来源的Gal-1更重要(附录3)。进一步的机制研究表明，Gal-1通过保护缺氧性肿瘤细胞免受凋亡，同时促进肿瘤内T细胞死亡来介导其促肿瘤作用。我们还发现，Gal-1是XPB1剪接所必需的，XPB1是未折叠蛋白(UPR)途径的调节因子。UPR是一种广为人知的促生存途径，几位研究人员报道了它可以保护癌细胞免受缺氧诱导的细胞死亡。基于这些数据，合理地询问 以下问题：(1)IRE1/XBP1通路是否介导了Gal-1诱导的肿瘤细胞凋亡；(2)靶向Gal-1的RT和化疗是否增加了缺氧性NSCLC的肿瘤控制？本研究的一个主要目的是了解Gal-1在缺氧肿瘤细胞中的促生存功能，并确定靶向该蛋白是否会增加缺氧NSCLC的RT疗效。一种常见的临床观察是，RT经常会导致癌症患者严重的淋巴细胞减少&这种效应的确切机制尚不清楚。我们假设RT诱导Gal-1分泌，进而导致全球T细胞凋亡，导致淋巴细胞减少。这项建议的第二个目标是研究Gal-1在RT介导的淋巴细胞减少中的作用，并确定阻断Gal-1是否会改善这种影响。我们将使用3个具体目标来解决上述目标。在目标1中，我们将评估IRE1-XBP1通路在Gal-1介导的缺氧条件下肿瘤细胞凋亡中的作用，并确定XBP1的激活是否充分和需要这一过程。在目标2中，我们将确定抑制Gal-1的表达或抑制其功能(封闭抗体或抑制性二糖)是否会增强非小细胞肺癌细胞系和小鼠原位肿瘤的RT和顺铂化疗效果。此外，我们将通过T细胞耗尽实验来确定这种效应是否依赖于肿瘤的氧合和小鼠具有完整的T细胞功能。最后，在目标3中，我们将利用基因匹配的Gal-1缺陷肿瘤和Gal-1缺陷宿主的组合，确定Gal-1肿瘤或宿主的表达是否是RT诱导的淋巴细胞减少所必需和必需的。我们还将在实体癌放疗患者中将循环Gal-1水平与外周T淋巴细胞水平相关联。这些研究将有助于确定Gal-1是一个新的靶点，可以与RT结合使用 目的提高非小细胞肺癌的治疗效果。