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Small Estrogen Doses Fight Drug-Resistant Tumor Cells

Small Estrogen Doses Fight Drug-Resistant Tumor Cells

PHILADELPHIA—V. Craig Jordan, OBE, PhD, DSc, of Fox Chase Cancer Center, has received a $10.7 million grant from the Department of Defense (DoD) Breast Cancer Research Program for a Breast Cancer Center of Excellence focused on developing a new treatment model for breast cancer to reverse the eventual development of resistance to antiestrogen therapy, including an intriguing strategy that involves the use of very small doses of estrogen itself.

Four Task Teams

The 5-year multidisciplinary project, intended to encompass both laboratory research and clinical trials, involves scientists and physicians at Fox Chase and three other institutions, representing four task teams. Lori J. Goldstein, MD, director of Fox Chase's multidisciplinary Breast Evaluation Center, is Dr. Jordan's co-principal investigator for the new Center of Excellence grant. Dr. Jordan is vice president and scientific director of medical science at Fox Chase and holds its Alfred G. Knudson Jr., MD, PhD, Chair in Cancer Research.

Dr. Jordan is known as the "father of tamoxifen" for his seminal work that led to the validation of tamoxifen as a therapy targeted to treat breast cancer and the first drug used to prevent breast cancer. Much of Dr. Jordan's 35-year research career has focused on the selective estrogen-receptor modulators (SERMS) that act like estrogen in some ways but not in others. These drugs can bind to the hormone receptors found in breast cells and thus block the effects of natural estrogen.

The research to be conducted under the DoD grant takes advantage of the discovery that breast cancer cells devise complex survival strategies in response to estrogen-blocking drugs. "There is a need for a new strategy to reserve the eventual development of antihormonal drug resistance, to ensure that effective agents can ultimately be used indefinitely," Dr. Jordan said.

Dr. Jordan's laboratory studies have shown that these drug-resistant cells can now be killed by tiny doses of actual estrogen. In resistant cancer cells, the estrogen no longer stimulates growth but rather triggers rapid apoptosis.

Fox Chase researchers will work with the task teams and biostatisticians at Georgetown University's Lombardi Comprehensive Cancer Center and the Translational Genomics Research Institute in Phoenix to create a unique subcellular map of the new biology of estrogen that results in rapid apoptosis. Then Fox Chase and the task team at Johns Hopkins University will conduct phase I and II clinical studies to evaluate estrogen-induced apoptosis in the tumor.

"The centerpiece of our effort is the clinical trials consortium enhanced with consumer advocate participants from the Y-Me National Breast Cancer Organization, Susan G. Komen Foundation, National Breast Cancer Coalition, and Research Advocacy Network," Dr. Jordan said. "No single site or clinical organization alone can recruit the necessary number of patients for these trials without the partnership of advocates."

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