Understanding IGF-1: Jefferson Researcher Sees Drug Potential In Targeting Enzyme

And for good reason.

Hehas labored for years over trying to understand and detail the behaviorof insulin-like growth factor-1 (IGF-1) receptor, a protein which playsan important role in tumor growth. Several years ago he and hisco-workers discovered that normal cells lacking the IGF-1 receptor genecould not be made to turn cancerous. He found that when they “knockedout” 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 ideaof killing cancer cells, he says.

According to Dr. Baserga, whois professor of microbiology and immunology at Jefferson MedicalCollege of Thomas Jefferson University in Philadelphia and actingdirector of Jefferson’s Kimmel Cancer Center, in the past few years,scientists have learned that the IGF-1 receptor is also a key growthfactor that regulates cell and body size. Deleting the genes for theIGF-1 receptor and its docking protein IRS-1 result in mouse and flyembryos that are only 50 percent of normal size.

“This tells youin essence that the IGF-1 receptor and its docking protein control 50percent of body size in a non-redundant way,” he says. “This was animportant finding because it established the role of IGF-1 receptor andIRS-1 in controlling body size.”
Reporting August 19, 2005 in theJournal of Biological Chemistry, Dr. Baserga and his co-workers provideone possible molecular explanation for how this occurs.

Theyfound 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 thefirst ones to discover that IRS-1 goes to the cell nucleus, where itbinds a protein, ß-catenin, in the nucleus that regulates RNApolymerase 1, the enzyme that controls cell size,” he explains.

Hedoesn’t think that IRS-1 is the exclusive activator, but rather, one ofseveral. “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 tomake cells proliferate. Cells without the IGF-1 receptor can grow.”
Severalyears ago, Dr. Baserga, who pioneered much of the understanding of thebasic behavior of the IGF-1 receptor, and his co-workers used knockouts– specially bred mice lacking a particular gene – to develop a cellline without IGF-1 receptors. Normal cells grew, but would not turncancerous when placed in rodent cells with added cancer-causing genes.

Thefinding suggested that if cells that lacked IGF-1 receptor could not beturned cancerous, perhaps cancerous cells with IGF-1 could be reversed.
“If this is true in humans, then this is a rational target,” hesays. Studies by companies in the last few years have found thatantibodies and various small molecules made to the IGF-1 receptor killcancer cells without toxicity, he notes.

“The general idea isthat if you find something that knocks out the IGF-1 receptor, you willkill the cancer cells and have only a modest effect on normal cells –at least using cells in culture and in mice,” he says. Several yearsago, for example, Dr. Baserga and his group used antisense therapy totarget the IGF-1 receptor, which killed cancer cells in mice but didn’twork as well in people. However, clinical trials are just beginning, hesays, and he is still hopeful that other approaches will work in humans.

Inthe meantime, pharmaceutical companies continue to pursue potentialdrugs and small molecules that target the IGF-1 receptor, and stillseek Dr. Baserga’s help.