An anti-angiogenesis agent plus an agent that blocks a cell survival pathway show promise against breast cancer based on work in mice with expression of the Her2/neu oncogene, according to an article in the October 3rd issue of the Proceedings of the National Academy of Science.

The American research group had previously worked with a strain of mice that lacked expression for genes that encode proteins necessary for angiogenesis, called Id proteins. The experimental mouse strain has 2 of 4 Id genes inactivated and shows clinically deficient angiogenesis. When the researchers had transplanted malignant tumors into the mice, tumor growth either slowed or actual regression occurred.

In the current work, researchers began with 2 strains of mice, the strain with defective angiogenesis and a strain that had active expression of the Her2/neu oncogene and developed aggressive breast cancers in 100 percent of offspring. When the strains were mated, all of the offspring developed breast cancer. However, the characteristics of the tumors were distinctly different.

Paola de Candia, PhD, lead author, said "It was unexpected that the tumors would be able to overcome an inhibition to angiogenesis. The mice developed large tumors despite the impairment in their ability to form new blood vessels caused by Id deficiency. The tumors were morphologically different with cystic centers and a narrow rim of tumor cells. The cells in the rim continued to proliferate and invade tissue. Ultimately, they metastasized, suggesting that inhibiting tumor angiogenesis was not sufficient to suppress tumor growth and progression.”

The researchers hypothesized that tumors require stress-induced survival pathways in order to maintain the expression of the Her2/neu oncogene and to proliferate. Because the Hsp90 chaperone protein is required to activate these pathways, the investigators tested the effects of an Hsp90 inhibitor called 17-AAG on the growth of the tumors in the crossbred mice.

Mice were randomly assigned to 17-AAG treatment or to control care when the first palpable tumor reached 5 mm in size. The anti-tumor effect of 17-AAG in the mice was dramatic: Growth of the unusual tumors was completely inhibited. The same drug caused reduced tumor growth rates but no dramatic responses in the mice with oncogene expression and normal angiogenesis function (normal Id genes).

David Solit, MD, study coauthor, commented on these findings: “When mice with aggressive breast cancer were treated with 17-AAG, a drug that inhibits the Hsp90 protein, tumor growth was slowed but not completely suppressed. However, when 17-AAG was administered to Id deficient mice which are unable to form functional new blood vessels, tumor growth was completely inhibited. The enhancement of the drug’s activity when combined with an anti-angiogenesis model suggests that cells with an impaired vasculature may be more dependent on the Hsp90 chaperone function for survival due to their low nutrient and low pH environment. This provides a rationale for combining anti-angiogenic and Hsp 90 inhibitors in clinical trials for patients with advanced breast cancer.”

"Because we have been able to create more sophisticated mouse models that overexpress the oncogenes found in 25 to 30 per cent of human breast cancer, these models are much more reliable in evaluating drugs," said Robert Benezra, Ph.D., senior author of the study. “The mice are more similar to humans with breast cancer so we are hopeful that our results will be able to translate into clinical trials.”