Mien-Chie Hung, PhD

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. Hung and Hortobagyi 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. Hung and Hortobagyi'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:
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 to numerous publications and research endeavors, 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.