Validation of Galectin-3 as a Target in Cancer Therapy

描述(由申请人提供)： Galectins是最近发现的一个进化保守的家族 -与半乳糖苷结合的动物凝集素。家庭成员参与了 免疫调节，诱导和抑制细胞死亡，细胞周期控制， 细胞黏附和与肿瘤的相关性。目前的趋势表明， Galectins将作为重要的诊断试剂、预后指标和 治疗多种肿瘤疾病的药物。 我们已经确定Galectin-3是一个潜在的干预分子靶点。 在几种肿瘤类型中。该蛋白在甲状腺癌中上调， 肝细胞癌和某些类型的淋巴瘤：正常甲状腺 上皮细胞、肝细胞和淋巴细胞不表达Galectin-3，但 相应的癌组织高度表达这种蛋白质。我们有 半乳糖凝集素-3‘S参与促进白血病细胞增殖 肿瘤细胞株在亚最适生长条件下的生长，并在抑制 细胞凋亡。许多化疗药物通过诱导细胞凋亡发挥作用， 而Galectin-3可以合理地被预期有助于治疗 由于其在调节细胞凋亡中的作用而产生的抗性。近期 高通量筛查数据表明，肿瘤细胞的化疗敏感性是 与Galectin-3表达水平呈负相关。Galectin-3也有 已证明在同型细胞黏附和细胞黏附中起作用 细胞外基质蛋白。此外，通过转基因实验， 其他研究人员发现Galectin-3的表达与肿瘤转移有关 癌细胞的财产。因此，Galectin-3的抑制剂可能对 癌症的治疗和我们的应用寻求验证Galectin-3作为一种 潜在的治疗目标，具体目标如下： 1.半乳糖凝集素-3表达抑制剂的研究进展Galectin-3特异性 反义寡核苷酸将被产生并用于抑制 Galectin-3蛋白在细胞中的表达。这些抑制剂对血管紧张素转换酶的影响 将评估肝细胞癌细胞的生长和凋亡情况。 2.Galectin-3功能抑制剂的研究进展寡核苷酸配体 Galectin-3选择性中和Galectin-3的(适配子) 功能将被选中。Galectin-3的多肽抑制剂也将是 通过噬菌体展示技术进行鉴定。这些抑制剂的作用 癌细胞与细胞外基质蛋白的黏附与侵袭 将对癌细胞的特性进行评估。

DESCRIPTION (provided by applicant): Galectins are a recently recognized family of evolutionarily conserved -galactoside-binding animal lectins. Family members are involved in immunomodulation, induction and inhibition of cell death, cell cycle control, cell adhesion and association with tumors. Current trends indicate that galectins will serve as important diagnostic agents, prognostic indicators and therapeutic agents for a variety of neoplastic diseases. We have identified galectin-3 as a potential molecular target of intervention in several tumor types. The protein is upregulated in thyroid carcinoma, hapatocellular carcinoma, and certain types of lymphomas: normal thyroid epithelial cells, hepatocytes, and lymphocytes do not express galectin-3, but the corresponding cancerous tissue express the protein highly. We have demonstrated galectin-3's involvement in promoting proliferation of a leukemic tumor cell line under suboptimal growth conditions, and in inhibition of apoptosis. Many chemotherapeutic agents function by induction of apoptosis, and galectin-3 may reasonably be expected to contribute to therapeutic resistance by virtue of its function in the regulation of apoptosis. Recent high throughput screening data suggest that chemosensitivity of tumor cells is inversely related to the levels of galectin-3 expressed. Galectin-3 has also been shown to play a role in homotypic cell adhesion and adhesion of cells to extracellular matrix proteins. In addition, by transfection experiments, other investigators have related galectin-3 expression to the metastatic property of cancer cells. Thus, inhibitors of galectin-3 may be useful for treatment of cancers and our application seeks to validate galectin-3 as a potential therapeutic target with the following Specific Aims: 1. Development of inhibitors of galectin-3 expression. Galectin-3-specific antisense oligodeoxynucleotides will be generated and used to inhibit the expression of galectin-3 protein in cells. The effect of these inhibitors on cell growth and apoptosis of hepatocellular carcinoma cells will be evaluated. 2. Development of inhibitors of galectin-3 function. Oligonucleotide ligands (aptamers) for galectin-3 capable of selectively neutralizing galectin-3 function will be selected. Peptide inhibitors of galectin-3 will also be identified by the phage display technology. The effect of these inhibitors on adhesion of cancer cells to extracellular matrix proteins and invasive properties of cancer cells will be evaluated.