siRNA Agents that Reduce Tumor Growth and Angiogenesis

This technology provides pharmaceutical or biotech companies siRNA anticancer drug candidates targeting a novel signal transduction pathway, and screening assays for further drug discovery against this target.

The researchers at Weill Cornell Medical College observed that xenografted tumor cells (LLC lung tumor and B16 melanoma) failed to grow in Galpha13 (the alpha subunit of an heterotrimeric guanine nucleotide-binding protein) heterozygous knockout mice while these tumors grow rapidly in wild-type littermates. They further discovered that Galpha13 is critical for growth factor-induced cell migration and angiogenesis. G-alpha 13 knockout in mouse embryonic cells blocked the growth factor-induced cell migration, while re-expression of a wild-type Galpha13 in cells rescued the migratory response to the growth factors. It was also discovered that G-alpha 13 regulates downstream from many receptors, therefore, might serve as a broader target. RNA interference was used to down-regulate the endogenous G-alpha 13 protein levels in wide-type mouse embryonic cells. Transfection of an siRNA against mouse G-alpha 13 significantly reduced the level of endogenous mouse Galpha13 protein, while transfection of a control siRNA did not change G-alpha 13 protein level. G-alpha 13 siRNA-treated cells also showed a defective cell migratory response to growth factor stimulation. A second siRNA against a different region of mouse G-alpha 13 gave similar results. Potentially, these siRNAs can be used as anticancer drug candidates.

Potential Application

Cancer therapeutics

Advantages

• Provide a new drug target
• G-alpha 13 regulates downstream from many receptors such as G protein-coupled receptors and growth factor receptors (receptor tyrosine kinases), therefore, might serve as a broader target than those receptors