Potential Breast Cancer Drug Target Identified

July 9, 2010 | Dagny Stuart

Cancer investigators at Vanderbilt-Ingram Cancer Center (VICC) have confirmed that a specific cell-signaling pathway, PI3-kinase (PI3K), in breast cancers may be a promising target for new therapies.

The study, led by Carlos Arteaga, M.D., professor of Medicine and Cancer Biology and leader of the VICC Breast Cancer Program, was published in a recent issue of the Journal of Clinical Investigation.

Todd Miller, Ph.D., research assistant professor of Cancer Biology, served as first author on the study.

Two-thirds of breast cancers depend on the female hormone estrogen for growth. Treatment options for those patients include antiestrogen drugs that block tumor cells from growing.

Todd Miller, Ph.D., left, and Carlos Arteaga, M.D., are investigating a cell-signaling pathway in breast cancer that may be a target for new therapies.

However, many women eventually develop resistance to those antiestrogen therapies and their tumors start growing again. In about 10 percent of those patients, this resistance is caused by high tumor levels of an oncogene called HER2.

The drugs trastuzumab (Herceptin) and lapatinib have been developed for use in those patients. But there is no effective treatment for the rest of the patients who develop resistance to endocrine therapies.

So Miller, Arteaga and colleagues developed and studied long-term estrogen-deprived derivatives from a panel of 4 ER-positive hormone-dependent breast cancer cell lines. These cell lines provide models of resistance to drugs called aromatase inhibitors, which are the most commonly used endocrine therapies in ER-positive breast cancer.

“We found that those cells exhibited increased activity in the PI3K/mTOR signaling pathway and that PI3K signaling was required for the cells to become hormone-independent,” said Miller.

“We were able to identify a protein signature of PI3K pathway activation in tumor biopsies that predicts poor disease outcome for women who have been on long-term endocrine therapy.”

The cancer researchers treated all four cell lines with an investigational drug (BEZ235), which has shown promising results in early trials. The drug, which blocks PI3K/mTOR, slowed or stopped growth in all of the cell lines and triggered cell death in three of the four cell lines.

The group also found that three of the four models retained the ability to grow even with low levels of estrogen.

This suggests that ending the use of an aromatase inhibitor drug in patients whose cancer progresses on this therapy may not always be wise. Eliminating the aromatase inhibitor may simply cause the body to resume estrogen production, stimulating the cancer.

“Our findings suggest that patients with hormone receptor-positive tumors exhibiting a high degree of PI3K signaling, and who relapse on endocrine therapy, may benefit from treatments targeting both the ER and the PI3K pathways,” explained Miller.

Other investigators included Yu Shyr, Ph.D., professor and Chief of the VICC Division of Cancer Biostatistics, and colleagues at MD Anderson Cancer Center and Novartis. The research was supported by grants from the National Institutes of Health, the Breast Cancer Research Foundation, the Kleberg Center for Molecular Markers, the American Society of Clinical Oncology and Stand Up To Cancer.

Photo by Susan Urmy

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