Pursuit of potential drugs and small molecules that target the IGF-1 receptor

Pharmaceutical companies around the world still come knocking on Renato Baserga, M.D.,'s door. And for good reason.

He has labored for years over trying to understand and detail the behavior of insulin-like growth factor-1 (IGF-1) receptor, a protein which plays an important role in tumor growth. Several years ago he and his co-workers discovered that normal cells lacking the IGF-1 receptor gene could not be made to turn cancerous. He found that when they "knocked out" IGF-1 receptors in cancer cells, the cells self-destructed, meaning the IGF-1 receptor was somehow necessary for tumor cell growth. Companies are interested in targeting the IGF-1 receptor with the idea of killing cancer cells, he says.

According to Dr. Baserga, who is professor of microbiology and immunology at Jefferson Medical College of Thomas Jefferson University in Philadelphia and acting director of Jefferson's Kimmel Cancer Center, in the past few years, scientists have learned that the IGF-1 receptor is also a key growth factor that regulates cell and body size. Deleting the genes for the IGF-1 receptor and its docking protein IRS-1 result in mouse and fly embryos that are only 50 percent of normal size.

"This tells you in essence that the IGF-1 receptor and its docking protein control 50 percent of body size in a non-redundant way," he says. "This was an important finding because it established the role of IGF-1 receptor and IRS-1 in controlling body size."

Reporting August 19, 2005 in the Journal of Biological Chemistry, Dr. Baserga and his co-workers provide one possible molecular explanation for how this occurs.

They found that when IRS-1 is activated with the IGF-1 receptor, ß-catenin, a protein important in colon and breast cancer is turned on. "We're the first ones to discover that IRS-1 goes to the cell nucleus, where it binds a protein, ß-catenin, in the nucleus that regulates RNA polymerase 1, the enzyme that controls cell size," he explains.

He doesn't think that IRS-1 is the exclusive activator, but rather, one of several. "It makes sense," he says. "When you knock out the IRS-1 gene, you get flies that are 50 percent in size, so there are other ways to make cells proliferate. Cells without the IGF-1 receptor can grow."

Several years ago, Dr. Baserga, who pioneered much of the understanding of the basic behavior of the IGF-1 receptor, and his co-workers used knockouts – specially bred mice lacking a particular gene – to develop a cell line without IGF-1 receptors. Normal cells grew, but would not turn cancerous when placed in rodent cells with added cancer-causing genes.

The finding suggested that if cells that lacked IGF-1 receptor could not be turned cancerous, perhaps cancerous cells with IGF-1 could be reversed.

"If this is true in humans, then this is a rational target," he says. Studies by companies in the last few years have found that antibodies and various small molecules made to the IGF-1 receptor kill cancer cells without toxicity, he notes.

"The general idea is that if you find something that knocks out the IGF-1 receptor, you will kill the cancer cells and have only a modest effect on normal cells – at least using cells in culture and in mice," he says. Several years ago, for example, Dr. Baserga and his group used antisense therapy to target the IGF-1 receptor, which killed cancer cells in mice but didn't work as well in people. However, clinical trials are just beginning, he says, and he is still hopeful that other approaches will work in humans.

In the meantime, pharmaceutical companies continue to pursue potential drugs and small molecules that target the IGF-1 receptor, and still seek Dr. Baserga's help.