Research: Synergy Spawns Success For Breast Cancer Research Team

When Dennis Slamon and Michael Press met on their first day of medical school at the University of Chicago in September 1970, they had no reason whatsoever to believe that their chance encounter would lead to a significant scientific advance. As it turned out, however, their friendship eventually led to a joint research effort that may provide a valuable genetic-based prognostic tool for breast and ovarian cancers.Thinking back to the day they met, Press recalls, "I was moving into the dormitory when I noticed this rather large person"--Slamon is six-foot-three--"struggling with an even larger foot locker. I asked him if he would like a hand toting the trunk. He said `yes,' and we've been friends ever since."That friendship, forged through several rigorous years pursuing a combined-degree curriculum (both men hold M.D. and Ph.D. degrees), became the basis for their professional partnership. In 1985, after years of musing about how much fun it would be to work together, Press, then a pathologist at the University of Chicago, teamed up with Slamon, a medical oncologist at the University of California, Los Angeles. The friends decided to join forces to zero in on the site along the cell wall where a protein produced by a leukemia retrovirus attaches itself. Since their long-distance collaboration worked out so well, Press decided to accept a faculty position at the University of Southern California so that he and Slamon could continue their research into the genetic triggers behind cancer.That move apparently paid off. In a cover story in Science (D.J. Slamon, et al., "Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer," 244:707-12, 12 May 1989), the team announced the results of its two-year study on ovarian and breast cancers to the scientific community. The team's findings revealed that the HER-2/neu proto-oncogene is amplified (that is, there are extra copies of the gene in the DNA of the tumor cell) in about 25 percent to 30 percent of human breast and ovarian cancers.The neu gene encodes a protein for a growth-factor receptor that promotes the aggressive growth of tumor cells. Cancer patients with HER-2/neu amplification in their tumors had a poorer prognosis, were more likely to relapse, and had shorter overall survival times than those without amplification. What is especially intriguing about the team's discovery is that the presence of the HER-2/neu gene may allow researchers to predict which women are most likely to have a recurrence of these types of cancer, even in the absence of other predictors of outcome, such as lymph node involvement. Since its publication, this groundbreaking study has attracted much interest from both the scientific community and the general public. This research sheds new light on the etiology and the biological links between two cancers that together account for one-third of all new malignancies in women and one-quarter of all the cancer deaths. (Each year, there are 110,000 new cases of breast cancer, and an additional 25,000 women are stricken with ovarian cancer.)"I think the reason our study has drawn so much attention is because the answers we and others are getting offer insights into a major disease that affects millions," says Slamon, settling into his desk chair in his small, sparsely furnished office."We took a team approach to this work simply because it would have been impossible for an individual to do this research in the period of time it was accomplished in," Slamon continues. The many researchers involved with this project also brought their different areas of expertise to the table. Pooling their talents augmented each scientist's work so that the whole became greater than the sum of its parts. One such researcher, Axel Ullrich, was the first to clone the HER-2/neu oncogene back in 1985. Ullrich, who was then a molecular biologist at Genentech Inc., in South San Francisco, Calif., is now the director of the molecular biology laboratory at the Max Planck Institute in Munich.Slamon's laboratory initially conducted the bulk of the research. This core group of about 15 research associates and laboratory technicians has been together since 1983. Later, Press's team across town at the University of Southern California and Ullrich's laboratory at Genentech, some 400 miles to the north, carried out some of the bench work. Says Slamon, "Mike Press or Axel Ullrich has expertise I don't have, and vice versa, and we can marry our techniques because we have common interests."The team brought in other researchers on an ad hoc basis, and Slamon leaned on fellow oncologists around the country to donate the breast and ovarian cancer tumor specimens that were so essential for the study. Slamon acknowledges that coordinating the logistics of a collaboration among seven different laboratories, some of which were located in Houston, Chicago, Vancouver, and the San Francisco Bay area, was often more nerve-wracking than negotiating Los Angeles' gridlocked freeways at rush hour. But what made it work, says Slamon, was the high level of cooperation among the different researchers--a cooperation that was free of the often-destructive competitiveness that tends to impede joint ventures.Indeed, friendship seems to be the linchpin of Slamon's style. The outgoing, informal Slamon--"Denny" to everyone, including his secretary--seems uncomfortable being in the spotlight. And he is scrupulous about sharing the credit for his team's discovery with his colleagues. It is this egalitarian managerial style that creates the synergistic working environment where everyone is inspired to do his or her best work, according to Ullrich."Dennis was willing--and had the energy, patience, and ability--to do some very boring but absolutely essential bench work that enabled us to say this alteration [in the neu gene] is a significant marker for the progression of disease," says Ullrich, interviewed by telephone from his office in Munich. "It's almost impossible to get technicians to just sit there and grind up 200 tumors because the work is so repetitive. But not only was Dennis able to motivate them, he did much of the work himself. Dennis is one of the most honest collaborators I've ever worked with," adds Ullrich, echoing the sentiments of Slamon's other collaborators. "I trust him implicitly. And because I don't feel compelled to hold things back, it promotes the progress and the success of the collaboration."Ullrich and Slamon's joint research began in 1985, when Slamon buttonholed Ullrich after the German-born molecular biologist gave a lecture at UCLA. Over pizza and beer at a nearby bistro, Slamon convinced Ullrich to share some of the probes--including one for the HER-2/neu oncogene--that Ullrich had cloned in his laboratory at Genentech.Ullrich had probes and Slamon had a bank of tumors, along with a complete history of each patient--it seemed like a match made in heaven. So after what Slamon humorously describes as "the usual Kabuki dance that goes on in the beginning when you're getting to know someone," the pair joined forces. And although Ullrich now works in Munich, he still collaborates with Slamon to some extent.Pathologist Press, who had plenty of experience examining tissue specimens, came aboard not long after, and the team was off and running. "At that time, Dennis had a thriving lab in a very small space--about 600 square feet--with about 15 people working in there," Press recalls. "The place was always packed and people worked round the clock. You practically had to take a number to get bench space--and if you left for a few minutes, someone would take your place. But the saving grace was that there was a tremendous esprit de corps because we were doing exciting, valuable work."The crowding has eased somewhat, thanks to the addition of Press's lab at USC. But the team members are still busy, burning up the phone wires with faxes and phone calls. They meet every week or so, gearing up for clinical trials, which they hope will begin within the next year.Beth Karlan, a gynecological oncologist at Cedars Sinai Hospital in Los Angeles and one of Slamon's former students, has been brought in to add her first-hand experience with patients. Her role will be to identify likely candidates, and to help design the trials. "We know the neu oncogene codes for a protein that promotes the growth of the tumor cells," explains Karlan. "The goal of the clinical trials is to use an antibody to regulate the tumor growth by affecting the protein's function."Meanwhile, Michael Shepard, a molecular biologist at Genentech, has spent the past several years developing just such an antibody. "That's been the beauty of this entire research effort," concludes Shepard. "There were so many first-rate scientists working simultaneously in key areas, and the team became a perfect complementary blend of all our talents. And the work is exciting because we think we've come up with a way of really doing something to effectively combat cancer."Linda Marsa is a freelance writer based in Los Angeles.

Research: Synergy Spawns Success For Breast Cancer Research Team

When Dennis Slamon and Michael Press met on their first day of medical school at the University of Chicago in September 1970, they had no reason whatsoever to believe that their chance encounter would lead to a significant scientific advance.

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