Targeting Galectin-1 with radiation in lung cancer

描述（由申请人提供）：非小细胞肺癌（NSCLC）是一种高致死率疾病。尽管适形放疗（RT）的剂量不断增加，但仍有很高的胸内失败率。需要一种新的方法来提高这些肿瘤的放疗效果。半乳糖凝集素-1 （Gal-1）是一种分泌的碳水化合物结合凝集素，以其在调节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起着重要作用。它在包括非小细胞肺癌在内的许多癌症中表达，其表达与肿瘤的侵袭性行为有关。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，这反过来又可以赋予肿瘤免疫。通过蛋白质组学分析，我们发现低氧和rt都能增强Gal-1的分泌。通过在非nsclc细胞系中下调Gal-1和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（附件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，从而介导其促瘤功能。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是一个众所周知的促生存通路，被一些研究者报道，可以保护癌细胞免受缺氧诱导的细胞死亡。基于这些数据，我们有理由问

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.