This revised proposal details a 4-year training program for the development of an academic career in cancer biology. Having recently completed clinical training in medical oncology, the Principal Investigator (PI) will use this dedicated period to acquire the knowledge and skills necessary to become an independent researcher. The PI will be mentored by a leading cancer biologist, Dr. Harold Varmus, who has trained numerous productive scientists. The Memorial Sloan-Kettering Cancer Center will provide institutional support. Ample resources and multiple career development activities will be available to help the PI achieve his goals. ? ? Research will focus on lung cancer, the leading cause of cancer-related mortality worldwide. The lab has developed a mouse model of lung cancer which shows that the continued expression of activated K-ras is required for the maintenance of lung tumors. This suggests that tumor cell death could be induced by targeting molecules that regulate this process. The studies proposed are designed to elucidate the mechanisms of lung tumor regression. The hypothesis is that lung tumor cells expressing the K-ras oncogene have undergone adaptive changes in gene transcription and/or protein expression such that they require the continued presence of activated K-ras for viability. Preliminary data suggest that major Ras signaling pathways and/or inhibitor of apoptosis proteins (lAPs) are probably involved. To study this further, we will use 2 experimental approaches: the lung cancer mice, and a more flexible model system that the PI has developed in which transformed murine embryonic fibroblasts (MEFs) also display dependence on activated K-ras for tumor survival. Although MEF and lung tumors are derived from different cell types, the MEF tumor regression model phenocopies that seen in the lung, suggesting that shared mechanisms may exist. Findings obtained from studies of MEF tumor regression will be verified in lung tumors.
Specific aims i nclude 1) determining if/which major Ras signaling pathways mediate activated K-ras-dependent tumor maintenance, and 2) assessing the impact of lAPs in maintaining tumor survival. The long-range goal is to identify molecular targets to induce apoptosis in human lung cancers. ? ?
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