Washington, D.C. -- Eliot Rosen, M.D., Ph.D., professor of oncology, biochemistry and cell & molecular biology, and radiation medicine at Georgetown Lombardi Comprehensive Cancer Center, has been awarded a $600,000 Investigator Initiated Research grant by the Susan G. Komen for the Cure®, an international breast cancer organization. The grant supports research on an entirely new class of treatment for a common type of breast cancer.
Most breast cancers are fueled by estrogen and are known as estrogen-receptor-positive (ER+) cancers. Drugs that prevent estrogen from stimulating the growth of the tumor cells (such as tamoxifen, an “anti-estrogen” drug) or that prevent the production of estrogen in the body (such as aromatase inhibitors like anastrozole) can keep the cancer at bay. Eventually, however, the cancer cells can learn to grow without the estrogen. Rosen’s research is aimed at finding ways to prevent the cancer cells from becoming resistant to anti-estrogen therapy.
“In our laboratory work, we found that the tumor suppressor protein from a gene called BRCA1, in addition to its previously described function in helping the cell to repair damaged DNA, physically binds tightly to the estrogen receptor protein-- inhibiting its activity and stopping the growth of ER-positive breast cancer cells,” says Rosen, who holds the Gragnani Chair in Oncology and Radiation Biology at Georgetown Lombardi, a part of Georgetown University Medical Center.
The tight binding observed by Rosen sparked an idea.
Based on years of prior work to characterize exactly how the estrogen receptor and BRCA1 proteins interact together, Rosen and his team created a computerized three-dimensional model of the binding interaction, then compared it to the design of small molecule drug-like compounds. They were looking for similarities with the specific portion of the BRCA1 protein that inserts itself deeply into the estrogen receptor protein. They found six compounds that bind to the estrogen receptor when it is also bound to tamoxifen, in the same manner as BRCA1.
“All six new compounds strongly inhibited the activity of the estrogen receptor at low concentrations,” Rosen explains. “Importantly, two of our compounds inhibited estrogen-receptor activity and cell growth in ER+ breast cancer cells that were resistant to tamoxifen and other anti-estrogens used clinically to treat breast cancer.”
Rosen says these compounds also — surprisingly— partially restored the cell’s sensitivity to tamoxifen.
The Komen for the Cure grant funds the critical next steps in Rosen’s research. He and his team must now fully characterize the mechanism of the six compounds in preclinical studies, the step before the agents can be studied in a clinical trial.
“After identifying one or two compounds that are both safe and effective in animal models of anti-estrogen-resistant breast cancer, we will carry out further preclinical studies that are necessary to advance these compounds as potential novel drugs for use in humans.”
Rosen points out that this area of research is particularly critical because current treatments either don’t work in a large number of patients with estrogen ER+ breast cancers or their tumors eventually develop resistance to therapy, leading to disease progression and death.
“We are hopeful that our compounds can be developed into drugs that will be useful both for breast cancer prevention and for treatment, particularly for anti-estrogen-resistant cancers, either by themselves or in combination with conventional anti-estrogen agents,” he says.
Rosen reports no potential financial conflict related to this work. The research described was previously funded, in part, by the Elsa U. Pardee Foundation of Michigan.
About Georgetown Lombardi Comprehensive Cancer Center
Georgetown Lombardi Comprehensive Cancer Center, part of Georgetown University Medical Center and Georgetown University Hospital, seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic and clinical research, patient care, community education and outreach, and the training of cancer specialists of the future. Georgetown Lombardi is one of only 40 comprehensive cancer centers in the nation, as designated by the National Cancer Institute, and the only one in the Washington, DC, area. For more information, go to http://lombardi.georgetown.edu.
About Georgetown University Medical Center
Georgetown University Medical Center is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through MedStar Health). GUMC’s mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis -- or "care of the whole person." The Medical Center includes the School of Medicine and the School of Nursing & Health Studies, both nationally ranked; Georgetown Lombardi Comprehensive Cancer Center, designated as a comprehensive cancer center by the National Cancer Institute; and the Biomedical Graduate Research Organization (BGRO), which accounts for the majority of externally funded research at GUMC including a Clinical Translation and Science Award from the National Institutes of Health. In fiscal year 2009-2010, GUMC accounted for nearly 80 percent of Georgetown University's extramural research funding.