Gabriel N. Hortobagyi, MD, FACP

2009-2010 BCRF Project:
Co-Investigator: Mien-Chie Hung, PhD, University of Texas MD Anderson Cancer Center

With BCRF support, Drs. Hortobagyi and Hung have completed two of their three proposed objectives to date and demonstrated that the therapeutic efficacy (anti-tumor activity and survival rate) of Endo-CD/5-FC is comparable or better than that of Avastin/5-FU in a mammary xenograft model; and Endo- CD/5-FC exhibited a safer profile than Avastin/5-FU in the laboratory model toxicity studies. These encouraging preclinical results suggest that Endo-CD protein therapy is a worthy candidate for future breast cancer clinical trials.

Signaling pathways and molecules such as AKT, ERK and MDM2 play important roles in the progression of breast cancer and all three molecules have been considered as excellent therapeutic targets. Multiple inhibitors of these three molecules have been developed by pharmaceutical companies and tested in clinical trials. Based on recent literature (1), and recent studies by Drs. Hortobagyi and Hung (Nature Cell Biology 2001; Nature Cell Biology 2008; Clinical Cancer Research 2009) (2-4), all three molecules were shown to down-regulate the tumor suppressor FOXO3a. Their preliminary results further suggest that FOXO3a may be used as a predictive marker of response to drug treatments and to explore the effect of ERK, AKT and MDM2 inhibitors, individually or in combination in breast cancer models. Success of this study may lead to the development of an effective combination therapy with a biomarker to predict response to therapy for breast cancer patients in the future.

Mid-Year Progress Report:
To further explore the role of FOXO3a as a predictive marker and develop effective combination therapy for breast cancer, the researchers have proposed two plans of actions in this current proposal. They have encouraging preliminary results in cell culture systems. Drs. Hortobagyi and Hung are pleased to report that they have validated FOXO3a activation as a predictor for sensitivity of cancer cells treated by AZD6244 (i.e. in support of the first plan of action they proposed); and identified combination therapies that are effective in inhibiting tumor growth and inducing cell death. They have submitted a manuscript entitled "Activation of FOXO3a is sufficient to reverse MEK inhibitor chemoresistance in human cancer", which is currently under review in Cancer Research.

Bio:
Gabriel N. Hortobagyi, MD, FACP is Professor of Medicine, Chairman of the Department of Breast Medical Oncology and Nellie B. Connally Chair in Breast Cancer at the University of Texas MD Anderson Cancer Center. He is also the Director of the Breast Cancer Research Program at the same institution. Dr. Hortobagyi has over 650 full-length publications in peer-reviewed journals; more than 350 invited papers; and over 140 book chapters to his credit.

He is recipient of the 1997 Brinker International Award, the 1999 Vermeille Medal of the City of Paris, France, and was named Chevalier of l'Ordre de la Légion d'Honneur de France in 2001. Dr. Hortobagyi received the Glen Robbins Award in Breast Cancer Research from the New York Cancer Society and the Metropolitan Breast Cancer Group in April 2003, the Bristol-Myers Squibb 2003 Horizon Scientific Award; in 2004 Dr. Hortobagyi was the Jeffrey A. Gottlieb Memorial Award recipient, and was honored as the first recipient of the Umberto Veronesi Award for the Future Fight Against Breast Cancer. In 2005, Dr. Hortobagyi received the medal of the Mexican Society of Oncology, and the Mario Rabinovich Prize in Argentina; in 2006, he received the Luigi Castagnetta Prize in Italy, and the Pathfinder Award of the American Society of Breast Disease. In 2007, he received the Beacon Award fromCancer Care in New York, the Cruz Civica Jorge Bejarano, in Colombia, and the keys to the City of Cartagena (Colombia). In 2007, Dr. Hortobagyi was the recipient of the Gold Medal for Contributions to Translational Research in Oncology, at the First International Conference "Translational Research in Oncology" in Forli, Italy, and in 2009, he was given the ASCO Statesman Award, the Charles A. LeMaistre Outstanding Achievement Award in Cancer and the John Mendelsohn Lifetime Scientific Achievement Award. He has also received two honorary doctorates: from the Universitá degli Studi di Modena E Reggio Emilia, Modena, Italy and from the La Universidad Autónoma de Nuevo León, Monterrey, México.

His professional society activities include membership in the American Society of Clinical Oncology, where he has served on various task forces, chaired committees, served on the Board of Directors, and in 2005 was elected President for the term 2006-2007. He chairs the Data and Safety Monitoring Committee of the National Surgical Adjuvant Breast and Bowel Project; and served as President of the International Society of Senology. He served as a member of the U.S. National Committee for the International Union Against Cancer, the National Cancer Institute's Breast Cancer Progress Review Group, co-chaired the Operational Efficiency Working Group, and chaired the Steering Committee of the Breast Health Global Initiative and the Health Advisory Board of the Susan G. Komen Breast Cancer Foundation, and was a member of the Integration Panel of the Breast Cancer Research Program of the Department of Defense. Dr. Hortobagyi is on the Executive Board of Scientific Advisors of The Breast Cancer Research Foundation and currently chairs the South West Oncology Group Breast Committee.