Blocking estrogen may be vitally important to improving survival from lung cancer

New and effective treatments for lung cancer may rest on their ability to hinder the action of estrogen in lung cancer cells, according to two studies published in the current issue of Cancer Research.

The University of Pittsburgh studies build on current knowledge about the relationship between estrogen and lung cancer growth and suggest that blocking estrogen may be vitally important to improving survival from the disease.

Since 1930, a 600 percent increase in death rates from lung cancer has been reported in women in the United States, leading some experts to suggest that women may be more susceptible to lung cancer than men. The current research contends that this could be due to the effects of estrogen on the lungs.

"Our studies continue to show that lung cancer cells grow in response to estrogen and that stopping or slowing the spread of the disease may be dependent on blocking the action of estrogen," said Jill Siegfried, Ph.D., professor, department of pharmacology and co-leader, Lung and Thoracic Malignancies Program, University of Pittsburgh Cancer Institute. "In fact, in previous studies, we have observed that lung tumor cells contain estrogen receptors at levels comparable to breast cancer cells." A receptor is a structure on the surface of a cell that selectively receives and binds substances.

In the first study, Laura Stabile, Ph.D., instructor in the department of pharmacology at the University of Pittsburgh, and colleagues examined methods to block the action of estrogen in human lung tumors grafted in mice. They compared the effect of blocking the estrogen receptor (ER) pathway alone to blocking it in combination with another receptor pathway – the epidermal growth factor receptor (EGFR). The investigators combined an agent approved for inhibiting the EGFR pathway, gefitinib (Iressa®), with an anti-estrogen agent, fulvestrant (Faslodex®) – a treatment commonly used to manage breast cancer in women with ER positive tumors, but not yet approved for clinical lung cancer treatment. They found that the combined treatment resulted in a tumor volume decrease of 59 percent, compared to a 49 percent decrease for gefitinib treatment alone and a 32 percent decrease for fulvestrant treatment alone. They also found that lung tumors in the combined treatment group were comprised mainly of dead and dying cells, while the number of these cells in the single treatment groups was significantly lower. The study suggests that an interaction between treatments that target both ER and EGFR may enhance the anti-tumor effects of therapy over the use of each agent alone. A pilot clinical trial is already underway testing the combination therapy in women with advanced lung cancer.

"Evidence from our study confirms what has been described for breast cancer – that blocking the estrogen receptor and the epidermal growth factor receptor pathways together is more effective," said Dr. Stabile.

In the second study, Pamela Hershberger, Ph.D., assistant professor in the department of pharmacology at the University of Pittsburgh, examined the effect of estrogen on the expression of genes in lung cancer cells. Using gene arrays, Dr. Hershberger and colleagues reported that some of the same growth genes induced by estrogen in breast cancer also are regulated by estrogen in lung cancer. In addition, the same estrogen inhibitor, fulvestrant, that was active against lung cancer in Dr. Stabile's study also blocked the ability of estrogen to regulate lung cancer cell gene expression. Dr. Hershberger's study further showed that other proteins needed for ER to act in breast cancer are found in lung cancer cells.

"Both of these studies clearly suggest that lung cancer cells respond to estrogen and that improving overall patient survival may be contingent upon identifying therapies that target specific pathways and put a halt to estrogen signaling," said Dr. Siegfried.

The studies were funded by a Specialized Program of Research Excellence (SPORE) award in lung cancer from the National Cancer Institute to the University of Pittsburgh Cancer Institute.

Co-investigators on the first study include Jennifer S. Lyker, Christopher T. Gubish, Weiping Zhang, Ph.D., Jennifer R. Grandis, M.D., and Dr. Siegfried. Co-investigators on the second study include Mark Nichols, Ph.D., A. Cecilia Vasquez, Beatriz Kanterewicz, Stephanie Land, Ph.D., and Dr. Siegfried.