Mien-Chie Hung, PhD

Drs. Hung and Hortobagyi 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. Hung and Hortobagyi 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:
Dr. Mien-Chie Hung is Professor and Chair for the Department of Molecular and Cellular Oncology at the University of Texas MD Anderson Cancer Center, Houston, Texas. He received his undergraduate and graduate degrees from the National Taiwan University in Taiwan and his Ph.D. from Brandeis University in Massachusetts. Currently, he also serves as the Director of the Breast Cancer Basic Research Program and is the Ruth Legett Jones Distinguished Chair. In addition, he is Professor, Department of Surgical Oncology, Distinguished Teaching Professor, and Director, Center for Biological Pathways.

Dr. Hung became a member of the Academia Sinica in Taiwan in July, 2002. Dr. Hung serves as a founding Editorial Members on Cancer Cell as well as an Associate Editor on Cancer Research, Clinical Cancer Research, Molecular Cancer Research and Molecular Carcinogenesis.

In recent years, Dr. Hung's laboratory has focused on signaling transduction pathways of tyrosine kinase growth factor receptors such as EGFR and HER-2/neu; molecular mechanisms of oncogenes -including transformation and tumorigenesis; and molecular mechanisms of tumor suppressor genes-mediated anti-tumor activities. His group made a critical breakthrough in showing that the transmembrane tyrosine kinase receptor EGFR can bind to a specific DNA sequence in the nucleus and that it functions as a transcription factor that can activate genes required for cell proliferation. Dr. Hung's group also demonstrated regulation of the cell cycle inhibitor p21 by the HER2/neu oncogene through phosphorylation of p21 by Akt, which results in changes in the subcellular localization.

The study provides a rationale for a long puzzling question surrounding p21--a cell cycle inhibitor that also associates with anti-apoptotic function. Furthermore, his group has demonstrated that an oncogene such as HER2/neu can suppress expression of the tumor suppressor gene p53 through the Akt/MDM2 pathways. The study provides a plausible mechanism showing that the p53 tumor suppressor gene, even without mutation, is frequently silent in oncogene-activated cancer cells such as HER-2/neu and Akt.

Most recently in the April 16th issue of Cell journal, Dr. Hung and co-workers have identified an important new tumor suppressor protein, FOXO3a (known as a longevity gene in some animal models) and a new oncogene, IKK (belongs to a family of enzymes called kinase) that provide targets for cancer therapy. Previously, these proteins had been suspected to be involved in cancer, but there was no direct evidence for that. Dr. Hung has demonstrated that IKK promotes tumorigenesis through inhibition of FOXO3a.

The other main research in Dr. Hung's laboratory is in cancer gene therapy that includes development of preclinical gene therapy animal models, including breast, ovarian and pancreatic cancers; identification of therapeutic genes suitable for cancer gene therapy; and development of gene delivery system for cancer gene therapy. Dr. Hung is the first person to demonstrate that adenovirus 5 E1A gene has anti-tumor ability in HER2/neu-over-expressing cancer cells by downregulation of HER2/neu overexpression. He is also a key person to actively drive laboratory research of E1A tumor suppressor gene into clinical trials (bench to bedside). Furthermore, Dr. Hung's laboratory is working on developing a tumor-targeted nonviral gene delivery system for human cancers such as breast, ovary, pancrease and prostate.