Shutting Off an On Switch: Novel drugs slow two cancers in mice

One way to arrest cancer is to identify a molecule that malignant cells just can’t do without—and then disable it. Researchers now report success with two experimental drugs that target such a protein, which triggers rapid growth and other malignant changes in cancer cells.

In mice, one of the drugs slows multiple myeloma, a lethal bone marrow cancer, and the other limits fibrosarcoma, a tumor of fibrous tissues. The scientists report their findings in two articles in an upcoming Cancer Cell.

The researchers homed in on the protein called insulinlike growth factor-1 receptor (IGF-1R). Recent studies have linked excess IGF-1R to heightened risks of colon, prostate, breast, lung, and bladder cancers. Although IGF-1R shows up on the surface of healthy cells, it’s more common on tumor cells.

When bound by its natural partner, insulinlike growth factor, the receptor triggers far-reaching processes within a cell that spur growth and disrupt self-destruction signals. Such activation of IGF-1R boosts healthy growth of normal cells but may also make malignant ones proliferate unchecked.

Earlier studies also indicated that cancerous cells respond to IGF-1R activation by spurring development of new blood vessels that nourish a growing tumor, says Andrew L. Kung of the Dana-Farber Cancer Institute and Harvard Medical School in Boston. Test-tube studies showed that inhibiting IGF-1R reverses cells’ malignant behavior.

To test whether IGF-1R inhibitors might stop cancer, Kung and his colleagues first injected mice with human multiple myeloma cells. After 3 weeks, the researchers began injecting some of the animals with twice-daily doses of an IGF-1R inhibitor called NVP-ADW742, while other mice got inert shots. After 19 days of this treatment, mice getting the inhibitor had smaller tumors; they also outlived their counterparts.

In the other study, researchers in Switzerland implanted fibrosarcoma tumors under the skin of mice. One week after implantation, one group of mice received twice-daily oral doses of an IGF-1R inhibitor called NVP-AEW541, while another group got an inert substance. Eleven days after the start of treatment, mice getting the drug had tumors about one-third the size of those in the mice receiving the placebo, says Francesco Hofmann, a biochemist at Novartis Pharma AG in Basel, Switzerland. The company developed the two IGF-1R inhibitors, and Hofmann was a coauthor of both reports.

The inhibitors disable a portion of IGF-1R that acts as an enzyme within cells, says Derek LeRoith, chief of the Diabetes Branch at the National Institutes of Health in Bethesda, Md. Researchers who took a similar approach to disrupting enzyme signals in tumor cells, he says, developed the anti-leukemia drug imatinib mesylate, also called Gleevec.

IGF-1R inhibitors don’t appear to eradicate cancer. But Kung and his colleagues have shown in lab-dish experiments that IGF-1R suppression works even against cancer cells that are resistant to conventional chemotherapy.