Mark I. Greene, MD, PhD, FRCP

2007-2008 BCRF Project:
A family of receptors (called the erbB family) that sits on the cell surface of breast cancer cells join together to form dimers either with same members (homodimers) or with different members (heterodimers), and these dimers augment the progression of breast cancer. Current therapeutics which target only an individual member of this family have limited value. Dr. Greene has found, through a structural and computer-aided process developed in his laboratory, small molecules that bind to these receptors and change the orientation of key surfaces, thereby disrupting their ability to form homo- or heterodimers. His project will study the mechanism of this interaction in order to improve the molecules so they can be developed into an oral therapeutic for breast cancer.

Mid-Year Progress Report:
Dr. Greene reports that his team has been successful in all aspects of the proposed aims. Their work has led to the identification and analysis of two new sets of drugs that have novel and remarkable activities on human tumor cells in vitro and in vivo. These drugs operate by a new principle of receptor inactivation. The drugs prevent erbB receptors from assuming a configuration that allows them to form a complex that causes malignancy. Initial studies show that the drugs work in vitro and in vivo to reduce human breast cancer cell growth. The researchers will focus on improving this class of drugs and learning how to use them in the most effective way to treat breast cancer.

Bio:
Mark I. Greene received his M.D. in 1972 from the University of Manitoba in Canada and his Ph.D. in Immunochemistry from the same institution in 1977. Mark Greene also received the FRCP from the Royal College in 1976. In 1976 Dr. Greene moved from Canada to Harvard University where he was a Medical Research Council Fellow. Professor Greene was appointed Assistant Professor of Pathology at Harvard Medical School and University in 1978 and rose to Associate Professor in 1980. Dr. Greene also served as a clinical consultant in Medicine at the Dana Farber Cancer Center from 1980-1986. Greene was recruited to Penn to head the Basic Research Unit of Immunology in 1986 and to create a Center for the Study of Receptor Biology. He also served on the Riken Institute Board of Scientific Advisors from 2000-2005 and was the Newton Abraham Professor of Medical Sciences, Oxford, from 2002-2003. He is currently a trustee of the Abraham Research Trust Unit at Oxford University.

Some of Greene's recent honors and awards include: the Guggenheim award, the induction into the Ashmolean Society, Master of Arts (Hon) Oxford University, Allyn Taylor Prize in International Medicine for the discovery of targeted therapy, and the Adams County Breast Cancer Research Award.

Mark Greene's laboratory developed an approach to target and down-modulate oncoproteins which, when expressed, were critical for abnormal growth. This simple approach developed in the neu system involved creating monoclonal antibodies specific for pl85, the product of the neu gene that his laboratory described with that of Robert Weinberg's. Greene found that he could disable the enzymatic activity of the receptor complex involved in malignant transformation with monoclonal antibodies. Moreover, down-modulation of normal receptors was not associated with cell injury. This was the basis for targeted therapy, and the approach has led to improved treatment for advanced breast cancer and to new therapeutics for the prevention of breast cancer emergence and reoccurrence.

Dr, Greene's current interests include the development of ultrasensitive diagnostics useful for early detection of breast cancer. He is also developing new orally available classes of targeted therapeutics that will function to treat both early and far advanced breast cancer with fewer toxicities.