Validation of Galectin-3 as a Target in Cancer Therapy

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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.