A primary goal of cancer research is to preferentially destroy tumors without harming normal cells. P27kip1 (p27) is a tumor suppressor protein commonly deregulated in aggressive cancers. Current models posit that p27 disruption leads to inappropriate cell cycle progression, so therapeutic intervention is geared towards the use of cell cycle inhibitors. However, our lab recently discovered that p27deregulation provides cancer cells with a growth advantage by altering nutrient metabolic pathways. We compared nutrient use over time in immortalized cells with and without p27. As expected, wild type cells were completely dependent on glucose and grew until it was depleted. Cells lacking p27 also initially used glucose, but when its levels dropped modestly they abruptly switched to the amino acid glutamine. This switch could provide a growth advantage to cancers with deregulated p27 by allowing amino acid metabolism during early tumorigenesis (before blood vessel formation). As the tumor grows and develops blood vessels, p27 function could be re-established to utilize plentiful glucose. We sought to exploit this switch to target tumors with deregulated p27 by artificially decreasing glucose levels with 2-deoxy-D-glucose (2-DG). This should preferentially force p27(-/-) cells to use amino acids, and these pathways can be specifically targeted using drugs affecting amino acid metabolism. Preliminary results indicate that cells lacking p27 can be preferentially killed without affecting viability of wild type cells, supporting further development of this drug treatment protocol for targeting aggressive cancers with deregulated p27.

Combining metabolic inhibitors to preferentially target cancers with deregulated p27

249th National Meeting (2015)

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