Knocking out the KRAS oncogene prevents aggressive colorectal cancer cells from forming liver metastases. PhD-student Niels Smakman disabled the KRAS gene using RNAi, proving it’s relation to colorectal cancer development.
Colorectal cancer cells depend on mutant KRAS for their invasiveness, metastatic potential and immune evasion. This makes mutant KRAS an interesting therapeutic target with great potential against metastatic colorectal carcinomas. Because COX-2 is a direct target of mutant KRAS, COX-2 inhibitors might block tumor growth. Smakman indeed showed the potential of COX-2 inhibitors in slowing down the development of liver metastases from colorectal and bladder cancer in mice.
As an additional therapeutic tool, Smakman investigated the tumor killing potential of a specific reovirus. It turns out that mutant KRAS sensitizes CRC cells to reovirus T3D induced apoptosis. However, the therapeutic efficacy of reovirus T3D against established liver metastases is hampered by the host immune system but can be increased by concomitant immunosuppression.
Thesis Niels Smakman: “Towards KRAS-directed therapy. Dependency of metastatic colorectal cancer cells on mutant KRAS.”
PhD advisor: Prof.dr. I.H.M. Borel Rinkes
Co-advisor: Dr. O. Kranenburg
31 March 2006 02:30 PM, Academiegebouw, Domplein 29, Utrecht