Mark I. Greene, MD, PhD, FRCP

2012-2013 BCRF Project:
(made possible by generous support from Play for P.I.N.K.)

Dr. Greene's team has focused on creating compounds that will be especially useful in overcoming resistance to treatments of human breast cancer based on targeting erbΒ family members, such as HER2 and EGFR, whose over-expression is associated with tumor growth. The first compound Dr. Greene created is a "loop body" that embeds a fragment of the HER2 protein itself into an antibody fragment and should be effective at inhibiting the cancer promoting interactions of all HER2 family receptors. The second compound is a clamp like molecule that inhibits the enzyme activity of EGFR; and, in theory, its use can be extended and optimized for treating HER2 tumors. In 2012-2013, Dr. Greene's team will continue to optimize the development of these compounds for use in clinical care.

Mid-year Progress: Dr. Greene's goal is to eradicate breast cancers by using compounds that inhibit the erbB receptors present on the surface of these cancer cells. His laboratory has crystallized a clamplike inhibitor attached to the kinase (active enzyme) part of the erbB receptor. Thus, they can now visualize the interaction at the atomic level, which allows them to better understand how it functions and enables them to improve it.

Bio:
Mark I. Greene received his MD 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, induction into the Ashmolean Society, Master of Arts (Hon) Oxford University, Allyn Taylor Prize in International Medicine for the discovery of targeted therapy, the Adams County Breast Cancer Research Award, and the Cotlove 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 p185, 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.

Greene also developed the use of disabling receptor complexes with two antibodies specific for distinct regions of the receptor proteins. This approach is now in phase 3 clinical trials world wide and appears useful in treating patients who are resistant to a variety of therapies including Herceptin. The development of a therapy that is useful in resistant tumors provides important insight into why resistance emerges in the first place.

Dr. Greene's 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. Dr. Greene's most current interests are to develop new insights into why tumors become resistant to therapy and how to prevent and treat these processes.