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Pioneers of Targeted Breast Cancer Therapy Win Nineteenth Annual Warren Alpert Foundation Prize.
Discovery of Protein Receptor Led to Development of Herceptin, the first target-directed cancer treatment for solid tumors
BOSTON, May 30, 2007 — Four scientists who were instrumental in developing a revolutionary treatment for breast cancer will be awarded the nineteenth annual Warren Alpert Foundation Scientific Prize today at a ceremony at the Four Seasons Hotel.
The Foundation honors H. Michael Shepard, PhD, Founder, President & CSO of Receptor BioLogix Inc., South San Francisco, California; Dennis Slamon MD, PhD, professor of medicine and director of clinical/translational research at UCLA's Jonsson Comprehensive Cancer Center; Axel Ullrich PhD, Director of the Department of Molecular Biology at the Max Planck Institute for Biochemistry, Martinsried, Germany; and Robert Weinberg, PhD, the Daniel K. Ludwig and American Cancer Society Professor for Cancer Research at the Massachusetts Institute of Technology-affiliated Whitehead Institute for Biomedical Research, in Cambridge, MA; for their role in the development of the breast cancer therapy Herceptin.
“Their work is an outstanding example of bench to bedside medicine that required incredible collaborative interaction among basic and clinical scientists,” said Joan Brugge, PhD, professor and head of the department of cell biology at Harvard Medical School and a member of the 2006 prize review committee.
Herceptin is a specially engineered antibody that inactivates a cell-surface protein, Her-2/neu, which promotes some of the most aggressive breast cancers. Since its approval by the FDA in 1998, Herceptin has been prescribed for hundreds of thousands of patients worldwide. In combination with chemotherapy, the antibody dramatically enhances the survival of patients with Her-2/neu-positive tumors, which account for about 25% of all breast cancers.
Her-2 (human epidermal growth factor receptor 2) and its mouse homolog neu (for neuroblastoma) are members of a family of receptor tyrosine kinases—a group of proteins that relay signals from outside the cell to the nucleus. Her-2/neu is also a proto-oncogene—meaning that a simple mutation of this one gene creates an oncogene, one that increases the likelihood that a normal cell will turn into a cancerous cell.
The story of Herceptin began in the late 1970s when Weinberg showed that normal mouse cells become cancerous when injected with snippets of DNA from rat tumors. One of those pieces of DNA caused neuroblastomas and was found to carry the neu oncogene. Weinberg’s group also showed that immunization against the neu protein protected mice from tumors induced by neu—the first sign that anti-neu antibodies might have some therapeutic benefit.
In the early 1980’s Ullrich’s cloning of the human epidermal growth factor receptor led to the identification of the closely-related Her-2, and when Ullrich and Weinberg both collaborated with Uta Francke at Yale University to pinpoint the chromosomal location of Her-2 and neu, they realized that they were working on homologs of the same protein.
Though Her-2/neu was recognized at that time as a proto-oncogene, its importance in breast cancer was not realized until Ullrich and oncologist Slamon collaborated to identify cell signaling pathways that have gone awry in various cancers. In a seminal 1987 Science paper, since cited over 4,000 times, the researchers reported that the levels of Her-2 are dramatically increased in about 25% of all breast cancers and that those cancers were also the most rapidly fatal. In subsequent studies Slamon and colleagues at UCLA showed that Her-2 was not simply a marker for aggressive cancers, but that there was a direct cause and effect relationship between Her-2 levels and tumorigenicity and metastasis. That work suggested that blocking the function of Her-2 with an antibody or other agent would be a viable therapeutic approach for treating human breast cancer.
With this in mind, Ullrich, and subsequently Shepard, worked at Genentech to develop a highly specific antibody that could be used as a human drug. They concentrated on a mouse antibody that inhibited tumor growth and also made tumor cells more susceptible to attack by the body’s own immune system. Because those mouse antibodies were not suitable for use in humans over the long term, Shepard and colleagues “humanized” the mouse Her-2 antibody by swapping some of its amino acids for those commonly found in human antibodies. That humanized mouse antibody eventually became known as Herceptin.
Herceptin was developed at a time where there was considerable scientific skepticism about the value of antibody-based therapies. “Mike Shepard is the person who really deserves an enormous amount of credit for keeping this project alive,” said Slamon. Shepard faced an uphill battle convincing Genentech to pursue this therapeutic strategy because at that time there were many researchers in the oncology field who did not believe that a large protein structure like an antibody could even gain access to cancer cells, which are often buried deep in human tissue. The company finally agreed to pursue the development of Herceptin when Shepard showed that once the Her-2 antibody is injected into human patients that it found its way to and bound to breast cancer tissue. Slamon and Shepard were then instrumental in running clinical trials and developing the combination Herceptin/chemotherapy that became so successful.
Herceptin has had an enormous impact on the field of oncology. “It is a paradigm for the whole idea of custom therapy, which is the future of cancer treatment,” said Brugge. Herceptin showed that a cell-targeted approach, as opposed to non-selective chemotherapy and radiation treatment, could be successful for solid tumors. Many other researchers and drug development companies followed the trail blazed by Herceptin and today there are many more targetedtherapies, some antibodies, others small molecules, that have been approved for cancer treatment.
The Warren Alpert Foundation
In awarding the sixteenth annual scientific prize to researchers who have made an impact on hepatitis therapy, the Warren Alpert Foundation has come full circle. Chelsea, Massachusetts native, the late Warren Alpert, first established the prize in 1987 after reading that Kenneth Murray of the University of Edinburgh had developed a successful vaccine for hepatitis B. Alpert decided immediately that he would like to reward such far-reaching breakthroughs, so he called Murray to tell him he had won a prize, and then set about creating the Foundation.
To choose subsequent recipients of the prize, Alpert asked Dr. Daniel Tosteson, then dean of Harvard Medical School, to convene a panel of experts to select and honor renowned scientists from around the world whose research has had a direct impact on the treatment of disease.
Each year the Foundation receives 30 to 50 nominations for the Alpert Prize from scientific leaders worldwide. Prize recipients are selected by the Foundation’s scientific advisory board, made up of internationally recognized biomedical scientists and now chaired by Joseph B. Martin, MD, PhD, Dean of Harvard Medical School.
The Foundation does not solicit funds. The scientific prize is funded solely by Alpert, chairman of Warren Equities.
Alpert, a first-generation American, started his business in 1950 with, as he told it, “$1,000 and a used car.” Today, Warren Equities and its subsidiaries—which market petroleum, food and spirits, and engage in transportation and real estate improvements—generate approximately $1 billion in annual revenue and have more than 2,200 employees in 11 states.
HARVARD MEDICAL SCHOOL
Harvard Medical School has more than 5,000 full-time faculty working in eight academic departments based at the School's Boston quadrangle or in one of 47 academic departments at 17 Harvard teaching hospitals and research institutes. Those Harvard hospitals and research institutions include Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Cambridge Hospital, the CBR Institute for Biomedical Research, Children's Hospital, Dana Farber Cancer Institute, Harvard Pilgrim Health Care, Joslin Diabetes Center, Judge Baker Children's Center, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, Massachusetts Mental Health Center, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, VA Boston Healthcare System.
CONTACTS
Judith Montminy
617-432-0442
public_affairs@hms.harvard.edu
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