Mark I. Greene, MD, PhD, FRCP
John Eckman Professor of Medical Science
Department of Pathology and Laboratory Medicine
University of Pennsylvania
2013-2014 BCRF Project:
(The Play for P.I.N.K. Award)
Dr. Greene's team will continue to improve compounds that they have found to be especially useful in overcoming resistance to breast cancer treatments of . They will target erbB family members such as HER2, EGFR, and HER4 whose overexpression is associated with breast tumor growth. The first series of compounds Dr. Greene's group has created are novel clamp-like orally deliverable small molecules, termed C318. These compounds inhibit the enzyme activity of normal and mutant erbB family members. The C318 set of compounds does not form irreversible linkages as do some other new types of HER2 inhibitors and, therefore, should not induce the significant human toxicities seen with these irreversible inhibitors. Dr. Greene's team will design and study the fifth generation with the goal of improving activity and bioavailability. The second set of therapeutics they have developed are new targeted monoclonal antibody-like proteins that are administered along with interferon-gamma (IFN-γ), a molecule known to be important in tumor control. This new therapeutic complex appears to possess the ability to inhibit growth of even resistant human breast tumors in model systems and will be further humanized for therapeutic application.
Dr. Greene’s goal is to eradicate breast cancer by using compounds that inhibit the erbB receptors present on the surface of breast cancer cells. His team now has synthesized and are testing the 5th generation of the clamp-like enzyme kinase inhibitors. They also recently discovered that interferon gamma (IFN-γ) added to the protocol at the same time or shortly after treating with the inhibitors that recognize the cell surface part of the erbB molecule is very beneficial. It prolongs inhibition of tumor growth and also makes the tumor more susceptible to genotoxic reagents (therapies that lead to cancer cell death) such as radiation or chemotherapy.
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.