Targeting Galectin-1 with radiation in lung cancer

用放射疗法靶向 Galectin-1 治疗肺癌

• 批准号: 8302668
• 负责人: ALBERT KOONG
• 金额: $ 32.68万
• 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/8302668
• 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. PUBLIC HEALTH RELEVANCE: This project focuses on targeting Galectin-1 (Gal-1), a carbohydrate binding protein, to improve the effectiveness of radiotherapy (RT) and chemotherapy in non-small cell lung cancer. It will teases out the mechanism by which Gal-1 protects cells from dying under hypoxia in order to optimize future targeting strategies. Finally, t investigates whether increased Gal-1 secretion by radiation therapy can cause a drop in the level of peripheral T-cells that is often noted in the clinic as a side effect of radiotherapy. It ill determine whether blocking Gal-1 function will help to improve RT success in patients with lung cancer while at the same time minimizing it's toxicity on normal circulating T-cells.

描述（由申请人提供）：非小细胞肺癌（NSCLC）是一种高致死性疾病。尽管适形放射治疗（RT）剂量递增，但胸内失败率仍然很高。需要一种新的方法来提高这些肿瘤的RT有效性。半乳糖凝集素-1（Galectin-1，Gal-1）是一种分泌型糖结合凝集素，其在调节T细胞稳态中的作用是众所周知的。最近，它已被证明在癌症进展中发挥重要作用。它在包括NSCLC在内的许多癌症中表达，并且其表达与侵袭性肿瘤行为相关。Gal-1参与了多种病理过程，包括肿瘤增殖、聚集、粘附、迁移、血管生成和增强T细胞凋亡，这反过来可以赋予肿瘤免疫。使用蛋白质组学分析，我们发现Gal-1分泌因缺氧而增强，最近又因RT而增强。在非NSCLC细胞系中下调Gal-1并在宿主小鼠中敲除该基因，我们发现肿瘤源性Gal-1在促进肿瘤生长和自发转移方面比宿主源性Gal-1更重要（附录3）。进一步的机制研究表明，Gal-1通过保护缺氧肿瘤细胞免于凋亡，同时促进肿瘤内T细胞死亡来介导其促肿瘤功能。我们还发现Gal-1是XPB 1剪接所必需的，XPB 1剪接是未折叠蛋白（UPR）通路的调节因子。UPR是一种众所周知的促生存途径，几位研究人员报道，以保护癌细胞免受缺氧诱导的细胞死亡。根据这些数据，合乎逻辑的是， 以下问题：（1）Ire 1/XBP 1通路是否介导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NSCLC的肿瘤控制？本研究的一个主要目标是了解Gal-1在缺氧肿瘤细胞中的促生存功能，并确定靶向这种蛋白质是否会增加缺氧NSCLC的RT疗效。 一个常见的临床观察结果是RT通常会导致癌症患者严重的淋巴细胞减少症&这种效应的确切机制尚不清楚。我们假设RT诱导Gal-1分泌，这反过来又导致全球T细胞凋亡，导致淋巴细胞减少症。该提案的第二个目标是研究Gal-1在RT介导的淋巴细胞减少症中的作用，并确定阻断Gal-1是否会改善这种影响。 我们将通过三个具体目标来实现上述目标。在目的1中，我们将评估Ire 1-XBP 1通路在缺氧条件下Gal-1介导的肿瘤细胞凋亡中的作用，并确定XBP 1活化是否是该过程所必需的。在目标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和顺铂化疗效果。此外，我们将确定这种作用是否依赖于肿瘤氧合和使用T细胞耗竭实验在小鼠中具有完整的T细胞功能。最后，在目标3中，我们将使用遗传匹配的Gal-1缺陷型肿瘤和Gal-1缺陷型宿主的组合来确定Gal-1肿瘤或宿主表达是否是RT诱导的淋巴细胞减少症所需的和必需的。我们还将在接受RT治疗的实体癌患者中将循环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 改善NSCLC的治疗结果。 公共卫生关系：该项目的重点是靶向半乳糖凝集素-1（Gal-1），一种碳水化合物结合蛋白，以提高非小细胞肺癌放疗（RT）和化疗的有效性。它将梳理出Gal-1保护细胞在缺氧条件下免于死亡的机制，以优化未来的靶向策略。最后，研究放射治疗引起的Gal-1分泌增加是否会导致外周T细胞水平下降，这在临床上通常被认为是放射治疗的副作用。它将确定阻断Gal-1功能是否有助于提高肺癌患者的RT成功率，同时最大限度地减少其对正常循环T细胞的毒性。