Disrupting two cell mechanisms in combination can suppress aggressive breast cancer in mice
Targeting angiogenesis alone not effective
Scientists at Memorial Sloan-Kettering Cancer Center and colleagues found that by inhibiting both the proteins responsible for breast cancer growth and those required for the formation of new blood vessels, they could more effectively suppress the growth of extremely aggressive breast tumors in mice. In a surprising finding, the researchers showed that mice harboring a mutation commonly found in human breast cancers developed tumors that were able to grow despite a defect in angiogenesis or new blood vessel formation. However, when these mice were also treated with a chemotherapy drug under development at Memorial Sloan-Kettering that inhibits Hsp90 (a cell survival protein), the chemotherapy was significantly more effective in the mice with abnormal angiogenesis so that tumor growth was completely suppressed. These findings, published in the October 3 issue of the Proceedings of the National Academy of Science, suggest that combining agents that target these two cellular functions should be evaluated for the treatment of advanced breast cancer.
"It was unexpected that the tumors would be able to overcome an inhibition to angiogenesis," said Paola de Candia, Ph.D., a researcher in the Benezra laboratory and first author of the study. "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 (liquid) 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."
In earlier research, the studys senior author, Dr. Robert Benezra, and colleagues had shown that mice with two of their four Id proteins genetically altered or "knocked out" had impaired angiogenesis which resulted in an inability to grow capillaries from existing blood vessels. When tumors were transplanted in these Id deficient mice, growth was either slowed or the tumors regressed.
For this study, transgenic mice were used that express the HER2/neu activated oncogene, a mouse model of breast cancer that is much more similar to human disease than transplanted tumors. This genetic modification leads to the development of aggressive breast tumors in 100 per cent of the cases. These mice were then crossed with mice that were Id deficient. The Id deficient, HER2/neu mice with abnormal angiogenesis developed breast tumors at the same rate as those with normal Id genes suggesting that Id deficiency and abnormal angiogenesis could not retard the growth of these HER2/neu dependent breast tumors. While the impairment in new blood vessel formation did not prevent tumor growth, the appearance of the tumors in the Id deficient mice was very different.
The researchers hypothesized that tumors require stress-induced survival pathways in order to maintain the expression of the neu oncogene and to proliferate. Since the Hsp90 chaperone protein is required to activate these pathways, they tested the effects of the Hsp90 inhibitor 17-AAG on the growth of the tumors. The mice were randomly assigned to 17-AAG treatment or control when the first palpable tumor reached 5 mm. The anti-tumor effect of 17-AAG in the Id deficient mice was dramatic with the tumor growth completely inhibited. This drug was only minimally effective in the mice with normal Id function.
"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," said David Solit, MD, a principle investigator of the 17-AAG trials and a researcher in the laboratory of Dr. Neal Rosen in the Cell Biology Program at Memorial Sloan-Kettering Cancer Center and co-first author of the study. "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 drugs 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."
The findings have implications for the design of future studies combining anti-angiogenic and Hsp90 inhibitor drugs in patients. "Because we have been able to create more sophisticated mouse models that over express 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, and head of a laboratory in the Cell Biology Program at Memorial Sloan-Kettering Cancer Center. "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."
This studys co-authors include Dr. Neal Rosen, Edi Brogi, Adam B. Olshen and Peter Siegel of Memorial Sloan-Kettering Cancer Center; Dr. Dilip Giri, Lifespan Academic Medical Center at Rhode Island Hospital; and Dr. William J. Muller of MOBIX , McMaster University. It was supported by the American Italian Cancer Foundation and the American Society of Clinical Oncology and by grants from the Breast Cancer Research Foundation and the National Institutes of Health.
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Joanne Nicholas | EurekAlert!