Targeting Galectin-1 with radiation in lung cancer

用放射疗法靶向 Galectin-1 治疗肺癌

• 批准号: 8826697
• 负责人: ALBERT KOONG
• 金额: $ 32.69万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8826697
• 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; Fractionated radiotherapy; 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。尽管适形放射治疗（RT）的剂量不断增加，但胸腔内失败率仍然很高。需要一种新方法来提高这些肿瘤的放疗效果。 Galectin-1 (Gal-1) 是一种分泌型碳水化合物结合凝集素，因其在调节 T 细胞稳态中的作用而闻名。最近，它已被证明在癌症进展中发挥着重要作用。它在包括非小细胞肺癌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，进而赋予肿瘤免疫力。通过蛋白质组学分析，我们发现缺氧以及最近的放疗可以增强 Gal-1 的分泌。通过在非 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 通过保护缺氧肿瘤细胞免于凋亡同时增强肿瘤内 T 细胞死亡来介导其肿瘤促进功能。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 是一种众所周知的促生存途径，据几位研究人员报道，它可以保护癌细胞免受缺氧诱导的细胞死亡。根据这些数据，可以合理地询问 以下问题：（1）Ire1/XBP1 通路是否介导 Gal-1 诱导的肿瘤细胞凋亡？（2）针对 Gal-1 的放疗和化疗是否会增加缺氧 NSCLC 中的肿瘤控制？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，并确定靶向该蛋白是否会增加缺氧 NSCLC 中的 RT 疗效。 一个常见的临床观察结果是，放疗通常会导致癌症患者出现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，进而导致整体 T 细胞凋亡，导致淋巴细胞减少。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 3 个具体目标来实现上述目标。在目标 1 中，我们将评估 Ire1-XBP1 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 XBP1 激活是否是该过程的充分和必需的。在目标 2 中，我们将确定抑制 Gal-1 表达或抑制其功能（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，我们将通过 T 细胞耗竭实验确定这种效应是否依赖于肿瘤氧合以及小鼠中完整的 T 细胞功能。最后，在目标 3 中，我们将使用基因匹配的 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必需的。我们还将在接受实体癌放疗的患者中将循环 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 是一种可与 RT 联合使用的新靶点 改善 NSCLC 的治疗结果。