were “turned on” or “turned off ” in cells with the mutant K-Ras, compared with the normal cells, as would be expected during the development of cancer. Among those “turned on” by K-Ras activation was a family of genes called PIM kinases. These genes, like K-Ras, are considered oncogenes — molecular entities that can cause cancer by helping cells grow uncontrollably. With further digging, Baines came across another paper showing that the first of the three members of this Pim kinase family, namely, Pim-1, was present at
abnormally high levels in samples from pancreatic cancer patients. He knew he had found his target. Before Baines could start going after Pim-1, he had to make sure that the previous findings pointing to its role in pancreatic cancer were all true. First, he used an advanced molecular technique called RNA interference that chops up K-Ras’ genetic message in the cell. When he watched to see how the loss of K-Ras affected the Pim kinases, he found that the activity of Pim-1, but not Pim-2 or Pim-3, went down. He then went on to confirm that there were indeed differences in this gene between normal and cancerous pancreas cells. “If you want to see if a gene would make a good drug target, you have to show that there is more of it in the tumor versus the normal, which we did,” said Baines, who has a joint appointment in the cancer research program at NCCU’s Julius L. Chambers Biomedical/Biotechnology Research Institute. “It meant we were on the right track.” If there are abnormal amounts of Pim-1 in pancreatic cancer, it follows that knocking out its activity could be a way to treat the disease. So Baines used his RNA interference technique again, this time targeting Pim-1 for destruction in the cell. He found that the loss of Pim-1 impacted crucial aspects of cancer development by reducing growth, decreasing invasion into neighboring tissue, and making cells more sensitive to radiation therapy.
The Way Forward
Baines is now collaborating with a number of pharmaceutical companies that have Pim kinase inhibitors in their pipeline to see if the drugs can stymie cancer
Disarming a time bomb
Pancreatic cancer is among the most lethal of cancers — the cause of one out of every four cancer deaths in the U.S., and difficult to detect until it has advanced and spread. Cancer is caused by sequences of chemical reactions known as signal transduction pathways, involving numerous proteins within cells. Researchers have known for decades that a key player in pancreatic cancer is a protein called K-Ras that controls cell growth. Normally, K-Ras works like a switch, turning on when growth is needed, and then shutting off, but a mutated form of the protein stays turned on, causing the uncontrolled growth and cell division that can lead to malignant cancer. Mutated K-Ras is present in 90 percent of all pancreatic cancers, but efforts to target it directly with drugs have not been successful. Researchers now seek to disrupt mutated K-Ras signaling indirectly by targeting proteins influenced by K-Ras activation. Antonio Baines has identified a target in a protein known as Pim-1, one of a family of proteins called Pim kinases. His research suggests that inhibiting Pim-1 holds promise as a way of disrupting the mutated K-Ras signaling, and thus disrupting the growth of pancreatic tumors. He is working with drug companies to see if a treatment can result from this research. 37
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