BioWorld International Correspondent

LONDON - Mopping up a molecule that is overabundant in colon tumors could be a viable way of treating colon cancer, a new study in mice suggested. The strategy relies on delivering the receptor to insulin-growth factor 2 (IGF2), which is produced in higher than normal quantities in several human tumors.

Bass Hassan, professor of oncology at the University of Bristol in Bristol, UK, told BioWorld International: "What we have shown is that challenging tumors that are dependent on IGF2 with a soluble IGF2 receptor works. This is an example of a logically directed cancer therapy of a type that is desperately needed in the clinic."

Hassan and his team have developed a therapeutic molecule for treating colon cancer, which is based on their understanding of the structure and function of the IGF2 receptor. The candidate therapy is under development with Cancer Research UK, the charity that funded Hassan’s work, and Cancer Research Technology, a technology transfer company that is wholly owned by Cancer Research UK.

The researchers hope to begin early clinical trials within two to three years.

A report of the study by Hassan and his colleagues appears in the Feb. 15, 2006, issue of Cancer Research in a paper titled, "Soluble IGF2 Receptor Rescues ApcMin/+ Intestinal Adenoma Progression Induced by Igf2 Loss of Imprinting."

IGF2 is known to be present at high levels in several common human tumors, including breast and bowel tumors, sarcomas and Wilm’s tumor. It is normally expressed during embryonic development, and at much lower levels during adult life.

The cell achieves tight control over expression of IGF2 by the process known as imprinting, whereby only one copy (allele) of the gene encoding IGF2 is transcribed. Such control is lost in about 10 percent of people, who produce IGF2 at levels twice that of normal, from both copies of their IGF2 genes. Those people apparently have normal colons. In people who have colon cancer, however, tests show that about 30 percent express IGF2 from both copies of the gene.

Studies on mice also suggested that IGF2 plays an important role in the development of colon cancer. In a mouse model of the condition known as human intestinal polyposis, which can develop into colon cancer, boosting levels of IGF2 can increase the risk of cancer developing, and increase the growth of the tumors that result.

Scientists have therefore been studying ways of knocking out IGF2 in order to stop cancer cells thriving on it. For example, several small-molecule inhibitors of molecules that operate downstream of IGF2 are in the pipeline.

Hassan, however, decided to try a different tack. He and his colleagues investigated what would happen if they put IGF2 out of action, using its receptor.

"The IGF2 receptor is a natural molecule that acts to clear the bioavailability of IGF2," Hassan said. "It marks IGF2 for degradation by the cell." Usefully, the IGF2 receptor also does not bind any other ligand (not even IGF1, which is very similar to IGF2), and it binds IGF2 with high affinity.

Because of the known association between loss of imprinting and colon cancer in humans, the team decided to cross the mice with the genetic predisposition to bowel polyps with mice that had no working copy of either the paternal or the maternal copy of the IGF2 gene. The result was mice with a genetic predisposition to bowel cancer, which expressed either no IGF2, or just one IGF2 allele (maternal or paternal), or both alleles.

Mice expressing double the normal quantities of IGF2 usually grow larger and develop colon tumors. But when Hassan and his colleagues delivered a gene expressing the IGF2 receptor into the animals’ intestines, the number and size of the adenomas significantly reduced.

Hassan said, "By overexpressing a transgene that manufactured the IGF2 receptor, which acts as a ligand trap and mops up IGF2, we were able to rescue the consequences of oversupply of IGF2."

The team is optimistic that work to modify the IGF2 "trap" molecule for therapeutic use could be completed within two or three years so that clinical trials can begin.

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