Obesity has been linked to breast cancer progression but the underlying mechanisms remain obscure. Here we report how leptin, an obesity-associated adipokine, regulates a transcriptional pathway to silence a genetic program of epithelial homeostasis i...
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Effective eradication of glioblastoma stem cells by local application of an AC133/CD133-specific T cell-engaging antibody and CD8 T cells
Local Immunotherapy of AC133+ Tumor Stem Cells
Rho kinase inhibitors block melanoma cell migration and inhibit metastasis
There is an urgent need to identify new therapeutic opportunities for metastatic melanoma. Fragment-based screening has led to the discovery of orally available, ATP-competitive AKT kinase inhibitors, AT13148 and CCT129254. These compounds also inhibit the Rho-kinases ROCK 1 and ROCK 2 and we show they potently inhibit ROCK activity in melanoma cells in culture and in vivo. Treatment of melanoma cells with CCT129254 or AT13148 dramatically reduces cell invasion impairing both "amoeboid-like" and mesenchymal-like modes of invasion in culture. Intravital imaging shows that CCT129254 or AT13148 treatment reduces the motility of melanoma cells in vivo. CCT129254 inhibits melanoma metastasis when administered 2 days after orthotopic intradermal injection of the cells, or when treatment starts after metastases have arisen. Mechanistically, our data suggest inhibition of ROCK reduces the ability of melanoma cells to efficiently colonise the lungs. These results suggest that these novel inhibitors of ROCK may be beneficial in the treatment of metastasis.