Mien-Chie Hung, PhD

With BCRF support, Drs. Hung and Hortobagyi 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. Hung and Hortobagyi (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.

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.