7 December 1998 CapCure5\Baserga.MS-- 825 words
IGF-1 receptor blocker cures 2 glioblastoma patients,
anti-sense sequence kills PCa cells in culture too
Lake Tahoe, NV--The body doesn't need insulin-like growth factor (IGF) to survive. But cancer cells do.
So interrupting the IGF pathway is another strategy for fighting cancer, said Renato Baserga, MD, who is professor and deputy director of the Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, PA.
Dr. Baserga recently completed a phase I study of 10 terminal patients with malignant glioblastoma, treated with an 18-mer oligonucleotide that targets the sequence of IGF-1 messenger RNA. It binds and activates an RNA-ase enzyme that destroys the mRNA.
Two patients had a "dramatic" long-term response, said Dr. Baserga. They "actually went back to work and regular activity." Four patients had an objective but transient response. Four had no response.
When the IGF receptor pathway is inhibited, normal cells may simply stop growing and become dormant, explained Dr. Baserga. But "tumor cells die immediately."
In normal cells, "the IGF-1 receptor is not an absolute requirement for growth" said Dr. Baserga. "It's a requirement for optimal growth."
"However, it is a requirement for anchorage-independent growth," said Dr. Baserga. "So it may work on tumor cells with minimal damage to normal cells."
"By now there is considerable evidence that the IGF axis is important for the growth of prostate cancer cells," said Dr. Baserga. "We are entering the field only now."
Even some of the researchers at CapCURE'S 5th Annual Scientific Retreat here this September were under the impression that IGF was necessary for survival, so they were surprised when Dr. Baserga flashed a slide of an IGF receptor knockout mouse. (The mouse, which had the gene for the IGF receptor disabled, was created by Argiris Efstratiadis of Columbia University, New York.)
But there is a human syndrome, Laron dwarfism, in which the IGF-1 receptor is absent, and African pygmies have low levels of IGF-1. "A good pediatrician will tell you that the levels of IGF-1 in the plasma is a good indication of how tall the child is going to grow, better than growth hormone itself," said Dr. Baserga. IGF-1 is produced by the liver in large quantities, and most cells have the receptor. "It is very important for adolescent growth," he said. "In the adult, it is important for renewal of tissues but it is not critical."
Dr. Baserga has been studying IGF-receptor knockout, or R-minus, cells. "We have made many mutants of the IGF-1 receptor," he said. So far, every transformed line behaves the same way.
It's hard to grow an oncogenic cell line without an IGF receptor even for laboratory studies. The R-minus mouse cells are "very refractory to oncogenic transformation," said Dr. Baserga. "Usually these mouse cells have the bad habit of transforming spontaneously. When we generated these R-minus cells we tried to transform them, and to our great surprise they didn't transform, even with powerful viral oncogenes." They finally managed to transform them with a v-src oncogene, which is "probably downstream from the IGF-1 receptor so that it can bypass it."
The IGF-1 receptor can take over some functions of the insulin receptor, said Dr. Baserga. "Genentech spent millions of dollars to try to use IGF-1 as a replacement for the insulin receptor."
"Insulin and IGF-1 have a lot of pathways in common, but IGF-1 has another pathway that the insulin does not have," said Dr. Baserga.
The R-minus cells are difficult to transform. "If I put an IGF-1 receptor back in, I can transform them," said Dr. Baserga, "but if I put in an insulin receptor I can not." That tells you that IGF-1 receptor is sending out a different signal.
The insulin receptor does protects transformed receptor-minus cells from apoptosis, though.
Another way to interrupt the IGF-1 pathway is with decoy receptors that compete for IGF-1 with the receptors on the tumor cell. Dr. Baserga recently published the results of one such study (Clin Cancer Res 1998 Nov;4(11):2647-55). The so-called dominant negative mutant, designated 486/STOP, caused growth inhibition and apoptosis of 5 different human tumor cell lines, and more important, killed neighboring cells with a bystander effect.
There's some evidence that, after most of the tumor cells are killed by IGF-1 starvation, the immune system of the host destroys the surviving cells. Immunocompetent mice have a durable resistance to tumor cells, while nude mice, which lack a cellular immune system, do not. "So I would hypothesis that antigenic peptides are released to induce an immune response to kill the survivors," said Dr. Baserga. "It looks like an immune response because the animals are immune for at least 1 year." But in order to prove that, he has to isolate the responsible peptides. "Until I isolate the peptide and show that it is immunogenic, my hypothesis remains a hypothesis."