Gabriel N. Hortobagyi, MD

Endostatin and angiostatin are two well-characterized endogenous angiogenesis inhibitors that have been shown to inhibit cancer growth in laboratory models in a cancer-angiogenesis specific manner without significant effects on normal vessel growth. These endogenous angiogenesis inhibitors exert their function by inhibiting the growth of cancer cells. Multiple clinical trials using endostatin/angiostatin as anti-cancer agents have been conducted in both the U.S. and China. Recently, the regulatory agency in China approved the use of endostatin as an anti-cancer agent for treating non-small cell lung cancer patients. However, the tumor suppressing effect of endostatin/angiostatin is mainly based on their inhibitory (cytostatic) activity on cancer cell growth rather than on their cell killing (cytotoxic) ability.

To further develop effective anti-cancer agents for breast cancer, Drs. Hortobagyi and Hung have recently generated preliminary results that show a fusion protein (Endo-CD) containing "cytostatic" endostatin--which retains its tumor targeting ability--and a "cytotoxic" protein, cytosine deaminase (CD)--that can convert the pro-drug 5-fluorocytosine (5-FC) into the chemotherapeutic drug 5-fluorouracil (5-FU)--exerts much stronger anti-cancer activity than either endostatin or CD alone in a model carrying mammary tumors. Based on their encouraging preliminary results, they intend to further develop the fusion protein concept to attain an effective therapeutic approach for breast cancer treatment.

In the coming year, the researchers will continue to study three important objectives that are critical for the development of this project into future clinical trials—whether there is prolonged survival in a dose-dependent manner in different laboratory models, to assess the safety of Endo-CD protein safety by determining toxicity in models, and to enhance therapeutic efficacy of Endo-CD by combining with other clinically used anti-cancer drugs including chemotherapeutics and molecular targeting drugs such as lapatinib (Tykerb), erlotinib (Tarceva) and gefitinib (Iressa). Successful outcomes of the current proposal may contribute to Endo-CD protein therapy for future clinical trials for breast cancer patients.

Mid-Year Progress Report:
As reported in Drs. Hortobagyi and Hung's last progress report in June 2007, the Endo-CD protein therapy exhibits strong anti-cancer activity in both cell culture and model studies. The results provide proof of concept that Endo-CD protein is associated with strong anti-cancer activity in mammary tumor model. However, the study used model Endo (endostatin) fused to CD (cytosine deaminase). To prevent potential side effects in future human clinical trials using model Endo, the researchers have now successfully expressed human Endo-fused CD. They now report that purified human endostatin proteins fused to CD do possess similar activities. Currently, we are pursuing three objectives by using the newly purified human endostatin protein linked to cytosine deaminase.

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 400 full-length publications in peer-reviewed journals; more than 300 invited papers; and over 100 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.

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, and the National Cancer Institute’s Breast Cancer Progress Review Group. Dr. Hortobagyi is on the Medical Advisory Board of The Breast Cancer Research Foundation, chairs 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.