Gabriel N. Hortobagyi, MD, FACP

Drs. Hortobagyi and Hung plan to develop a breast cancer-specific targeted therapy by using a fusion protein, namely, endostatin-cytosine deaminase. Multiple clinical trials have been performed with endostatin, and this protein has been approved by regulatory authorities as an anti-cancer drug in China.

The endostatin portion targets the tumor cells and carries the protein (CD) with it. The cytosine deaminase is important because it can take 5-fluorocytadine (5-FC), which is a well tolerated drug used to treat fungal infections, and change it to a very important and well-studied chemotherapeutic agent, 5-flourouracil (5-FU). By administering both the Endo- CD and 5-FC, the researchers' data demonstrated the Endo-CD effectively targeted the tumor cells and converted the prodrug, 5-FC to chemotherapeutic 5-FU that is delivered directly to the tumor cells. This would not only block the growth, but also kill the tumor cells and decrease the side effects that patients may suffer when exposed to chemotherapy instead of just targeting the tumor cells.

Based on promising preclinical results in cell culture and models showing that the anti-tumor activity of Endo-CD is much stronger than either component alone, thus it is worthy of moving into clinical trials. Success of this project will be translated into multiple clinical trials for metastatic breast cancer patients.

Mid-year Progress Report:
Drs. Hortobagyi and Hung continue efforts to move encouraging preliminary data of the endostatin-cytosine deaminase protein therapy into clinical trials for breast cancer patients. The endostatin protein, which was discovered by the late Judah Folkman in 1996, targets the endothelial cells of tumor tissues and is associated with the tumor-targeting, anti-angiogenic activity. Endo-CD associates with dual tumor-targeting activity, namely, tumor-targeting, anti-angiogenesis (from Endo) and tumor-targeting chemotherapy (from conversion of 5-FC to 5-FU by CD only in the tumor sites).

Both Avastin and 5-FU are FDA-approved drugs to treat breast cancer patients. The former is an anti-angiogenic drug (a monoclonal antibody against vascular endothelial growth factor (VEGF), an important factor for the growth of blood vessels from pre-existing vasculature) to shrink or inhibit blood vessel formation of tumors. However, both Avastin and 5-FU lack tumor-targeting capability, and they are often associated with unpleasant side effects as reported from clinical data. Therefore, the researchers have compared the effectiveness of treatment with Endo-CD and the two commercially available drugs combined-- Avastin with 5-FU—in laboratory models. They have found that the therapeutic efficacy of Endo-CD protein treatment is comparable to (or even better than) that of Avastin plus 5-FU in a laboratory model.

In addition, they also performed toxicity assays in models to test the kidney, liver and heart functions with Endo-CD or with Avastin. They found that Endo-CD has a safer profile than that of Avastin. Taken together, Endo-CD is warranted for moving into clinical trials-- a tumor-targeting activity with low or no toxicity in major organs including liver, kidney and heart.

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.