Validation of Galectin-3 as a Target in Cancer Therapy

描述（由申请人提供）： 半乳糖凝集素是最近认识到的进化上保守的半乳糖凝集素家族。 - 半乳糖苷结合动物凝集素。 家庭成员参与 免疫调节，诱导和抑制细胞死亡，细胞周期控制， 细胞粘附和与肿瘤的关联。 目前的趋势表明， 半乳糖凝集素将作为重要的诊断剂、预后指标和 用于多种肿瘤疾病的治疗剂。 我们已经确定半乳糖凝集素-3作为干预的潜在分子靶点 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半乳糖凝集素-3，但 相应的癌组织高度表达该蛋白。 我们有 证明了半乳糖凝集素-3参与促进白血病细胞增殖， 肿瘤细胞系在次优生长条件下， 凋亡 许多化疗剂通过诱导细胞凋亡发挥作用， 和半乳糖凝集素-3可以合理地预期有助于治疗 由于其在细胞凋亡调节中的功能， 最近 高通量筛选数据表明肿瘤细胞的化学敏感性 与半乳糖凝集素-3的表达水平呈负相关。 Galectin-3也 已经显示在同型细胞粘附和细胞粘附中起作用， 细胞外基质蛋白 此外，通过转染实验， 其他研究者认为半乳糖凝集素-3的表达与转移性乳腺癌有关， 癌细胞的特性。 因此，半乳糖凝集素-3的抑制剂可用于 我们的申请试图验证半乳糖凝集素-3作为治疗癌症的药物。 具有以下特定目的的潜在治疗靶点： 1.半乳糖凝集素-3表达抑制剂的开发。 半乳糖凝集素-3特异性 将产生反义寡脱氧核苷酸并用于抑制 半乳糖凝集素-3蛋白在细胞中的表达。 这些抑制剂对 评价肝细胞癌细胞的细胞生长和凋亡。 2.半乳糖凝集素-3功能抑制剂的研究进展。 寡核苷酸配体 能够选择性中和半乳糖凝集素-3的半乳糖凝集素-3的（适体） 功能将被选中。 半乳糖凝集素-3的肽抑制剂也将被 通过噬菌体展示技术鉴定。 这些抑制剂的作用 对癌细胞与细胞外基质蛋白的粘附和侵袭性的影响 将评估癌细胞的性质。

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.