A study by researchers from the Georgetown Lombardi Comprehensive Cancer Center at Georgetown University Medical Center (GUMC) identifies a potential new combination therapy to “rescue” treatment sensitivity to fulvestrant in estrogen receptor positive breast cancers. The findings were published on May 15, 2010 as the cover story of Molecular Cancer Therapeutics.

Fulvestrant is a common second-line therapy for women whose cancer progresses following anti-estrogen therapy. In this paper, Lombardi researchers identify a cytokine, a small protein called IFNγ, which appears to increase or even rescue sensitivity to fulvestrant.

Led by Robert Clarke, PhD, DSc, professor of oncology and physiology & biophysics at Lombardi, the research team identified a key downstream regulator of sensitivity to fulvestrant – the protein IRF1. When cells were treated with both fulvestrant and IFNγ, Clarke and colleagues saw an increase in expression of IRF1, which resulted in increased apoptosis - or programmed cell death - of the cancer cells.

The American Cancer Society estimates that in 2009, 192,000 women were diagnosed with invasive breast cancer, and approximately 70 percent of these cases were considered to be estrogen receptor-positive (ER+), meaning that estrogen and its receptor drive the disease. While a number of anti-estrogen therapies are able to successfully treat these cancers, resistance may develop, often leading to disease progression.

“This finding is significant because we and others in the field have been searching for a long time for clinically relevant ways to make anti-estrogen therapies more effective for women with ER+ breast cancer,” says Rebecca Riggins, PhD, assistant professor of oncology at Lombardi and co-author of the paper.

Most of the genes and proteins regulated by the estrogen receptor are unknown, and the molecular effects of therapies such as anti-hormonal drugs are also largely unidentified, says Clarke, who also serves as interim director of GUMC’s Biomedical Graduate Research Organization.

However, in this paper, the research team has identified that the induction of IRF1 expression involves regulation of well-known cell fate proteins including NF- κB and the BCL-2 family of proteins, leading to apoptotic pathways. Ultimately, Clarke and colleagues suggest that a combination of anti-estrogens and compounds that up-regulate IRF1 expression – like IFNγ – may be useful for the treatment of anti-estrogen resistant ER+ breast cancers.

Clarke was also recently awarded a major program grant by the National Cancer Institute to lead a Center for Cancer Systems Biology addressing estrogen receptor signaling in breast cancer resistance.

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In addition to Clarke and Riggins, authors include Yanxia Ning, Shanghai Medical College, Fudan University, Shanghai, P.R. China; Jennifer Mulla, Lombardi Comprehensive Cancer Center, Georgetown University; Haniee Chung, Lombardi Comprehensive Cancer Center, Georgetown University; and Alan Zwart, Lombardi Comprehensive Cancer Center, Georgetown University.

The authors report no related financial interests.

Grant Support
China Scholarship Council and National Natural Science Foundation of China State Scholarship Fund postdoctoral fellowship grant 30900716 (Y. Ning), Susan G. Komen Foundation postdoctoral fellowship grant PDF0503551 (R.B. Riggins), and Susan G. Komen Foundation grant KG090245 and U.S. Department of Health and Human Services grant R01-CA131465 (R. Clarke). Technical services were provided by Flow Cytometry, Macromolecular Analysis, Microscopy and Imaging, and Tissue Culture Shared Resources, which are supported by Public Health Service award P30-CA-51008 (Cancer Center Support Grant to the Lombardi Comprehensive Cancer Center, Georgetown University). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked Advertisement.

About Lombardi Comprehensive Cancer Center
The 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. 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 Georgetown’s affiliation with 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 nationally ranked School of Medicine and the School of Nursing and Health Studies, the world-renowned Lombardi Comprehensive Cancer Center and the Biomedical Graduate Research Organization (BGRO), home to 60 percent of the university’s sponsored research funding.

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