Successful management of melanoma will require eliminating both the primary cancer as well as its spread. The survival of melanoma patients reduces significantly if the cancer spreads to the brain. Five-year patient survival after melanoma spreads to brain is only 5%. The key contributor for growth of melanoma is changes in a protein called BRAF. Similarly, the major factor that influences melanoma to spread to the brain is a protein called AKT. To reduce cancer spread, a number of novel treatments are currently being evaluated. Our hypothesis is that targeting the AKT and BRAF pathways will reduce both cancer as well as its spread to the brain, by increasing an important protein, called p53. One such treatment strategy to achieve this is inhibition of AKT and WEE1, WEE1 being a downstream protein in the BRAF pathway. We have previously shown that targeting AKT and WEE1 is superior to targeting either of the proteins alone in reducing melanoma development. Therefore, the central hypothesis of this project is to test the effect of p53-modulation on melanoma metastasis to the brain. The project will be accomplished by first identifying the best strategy to target the p53 pathway using genetic modifications and drugs. The best identified strategy will be tested for its effect on the p53 pathway and regulation of growth of melanoma cells. Finally, this strategy will be evaluated to decrease melanoma growth and its spread to brains in a mouse model. This discovery would identify unique approaches to overcome melanoma brain metastasis thereby improving the survival of patients.