Medicine off the Midway
A cancer research pioneer, Slamon is shown here in the lab in his younger years.
Dennis Slamon, MD, PhD in his lab at UCLA. Photos provided by Dennis Slamon
CANCER
RESEARCH
GOES TO HOLLYWOOD
Just when it seemed the project might be sidelined, Slamon’s phone rang. It was Lilly Tartikoff, a prominent LA figure and anti-cancer activist with an eye for promising developments. The question for Slamon and coworkers was, “why?” Translational medicine — recognizing the two-way street between knowledge gained directly from working with patients and scientific findings emerging from the labs — has become well established since the 1970s, when the approach was being pioneered by Rowley, professor of molecular genetics and cell biology. Bringing together clinical experience with laboratory knowledge encouraged researchers to see that something had to be going on at the molecular level to explain the divergence in clinical outcomes. “There must be biology there,” Slamon said, recalling the fundamental insight. “It was understanding that there must be molecular diversity that caused the field to take a quantum leap forward.” The insight can be traced to one of Rowley’s early findings. Using ordinary scissors to snip apart photographs of abnormal cells from leukemia patients, she was able to demonstrate in 1972 that bits of separate chromosomes had broken off and
By Don Reneau
Dennis Slamon makes a quiet impression. Especially for a famous Los Angeles physician whose work was featured recently in a film backed by major Hollywood star power. Slamon owes his fame to the lead role he played developing the drug Herceptin, a revolutionary treatment approved in 1998 for a common type of breast cancer. Sharing the credit seems to come naturally to the doctor. Among those he lists as contributors to the breakthrough development are research collaborators over the years and his advisors at the University of Chicago, where he earned PhD and MD degrees in 1974 and 1975. But Slamon reserves special mention for breast cancer patients themselves, women who agreed to take part in the early clinical trials leading to the Food and Drug Administration’s approval for the effective new drug. A professor of medicine and director, since 1988, of Clinical/ Translational Research at UCLA’s Jonsson Comprehensive Cancer Center, Slamon appreciates Southern California as a fine place to pursue his work. But Los Angeles has never replaced Chicago in his affections. The product of small-town life in western Pennsylvania, Slamon remembers Chicago as his eye-opening introduction to life in the big city. “It was a great time in my life,” he recalled. “Chicago was just a great city, with all the things a big city has to offer. But it had a blue-collar feel, with friendly people, and it worked very well for me.” Clearly a good match for the modest, determined, hard-working personal style for which Slamon has been noted throughout his career. Whatever the benefits of living in a major urban center, the real payoff for all concerned was the postgraduate training Slamon received at the University of Chicago. Exposure to the excellent faculty — Slamon recalled Janet Rowley, MD, Winston Anderson, MD, and Werner Kirsten, MD, in particular — was “more than educational. It was formative.” Working in Kirsten’s 32 For more information, call 1-888-UCH-0200 or visit uchospitals.edu
lab, Slamon helped identify an early example of the so-called oncogenes, or cancer-causing genes, which can be shown in experiments to be associated with malignancies. It was an “incredibly rich and robust environment for training people like myself, who would be armed to come at the problem from both sides of the fence.” The problem, in a nutshell, was the discrepancy between the apparent promise of chemotherapies based on new experimental findings in the laboratory, and the radically divergent patient outcomes being seen in the clinical setting of a hospital. “The one thing that kicked the whole process off,” said Slamon, “was that we had been using one-size-fits-all approaches.” The chemotherapy cocktails designed on the basis of lab experiments were being administered to patients based largely on where the cancer arose, in the lung, say, or in the breast. “What should have told us something was off was that the clinical outcomes were different,” he said. “Some people did incredibly well. Some people did incredibly poorly.”
Slamon with Jonsson Comprehensive Cancer Center Director Judy Gasson, PhD, left, and Lilly Tartikoff, right.
exchanged places. It was because of this translocation of partial chromosomes that normal genes turned into oncogenes. In their original location they had regulated cell division and growth. Now they were causing normal cells to become cancerous. This was the initial discovery of the link between cancer and genetic abnormalities, for which Rowley was awarded the Presidential Medal of Freedom in August 2009. Given the relatively primitive technology available to Rowley at the time, Slamon marvels at her accomplishment. Productive findings can be hard to come by even today, using sophisticated computer software to compare huge panels of cancer cell lines in an attempt to link observed abnormalities to the underlying genetic constitution of the cell. But the results are unambiguous. Just because cancers originate in the same organ does not mean they are alike. Biologically speaking, some breast cancers are more like ovarian cancers, some lung cancers more like sarcomas. How a malignancy develops in the clinical setting — and thus what kind of intervention might be developed to stop it and save a patient’s life — depends not on the affected organ but on the molecular makeup of the disease. Herceptin, the drug developed based on Slamon’s preclinical and clinical research, targets a genetic abnormality that appears in about 20 to 25 percent of breast cancers, affecting more than 200,000 women each year worldwide. In these cases the HER2 gene, once again a gene that in normal cells
regulates division and growth, appears in abnormal cells in too many copies, resulting in overly rapid growth and a cancerous tumor. Herceptin works by inactivating a protein produced by the HER2 gene, which triggers the excessive growth. Used in combination with chemotherapy, the drug has transformed a very aggressive form of breast cancer, for which little effective treatment had been available, into a highly treatable disease. Some patients seem to overcome the malignancy altogether, living cancer-free years later, while in others the progress of the cancer is significantly slowed. Taking advantage of the conceptual breakthrough afforded by a translational approach was one thing; generating the level of funding necessary to turn the idea into a treatment is quite another. This is where the Hollywood connection comes in. By 1989, Slamon and his team found themselves at a crossroads, armed with promising new data but encountering resistance from funding sources in government and industry. “We tried to explain to them that we were targeting not just the marker of tumor cells but something that was playing a role in causing the tumor cell behavior,” he said. “But even with all the data, there were lots of naysayers.” Just when it seemed the project might be sidelined, Slamon’s phone rang. It was Lilly Tartikoff, a prominent LA figure and anti-cancer activist with an eye for promising developments. Of course, it didn’t hurt that since 1982 Slamon had been successfully treating Tartikoff ’s husband, the television producer Brandon Tartikoff, for a recurrence of Hodgkin’s disease. (Tartikoff died in 1997.) Lilly Tartikoff turned to Ronald Perelman of Revlon, persuading him to set up an unusual donor arrangement in 1990 that helped put Slamon’s research over the top and continues funding cancer research to this day. It was not just having celebrity backers that led eventually to “Living Proof,” the 2008 film about Slamon and his groundbreaking work. The story itself — determined scientist perseveres in the face of powerful resistance, succeeding against long odds in the nick of time to save an innocent life — is the stuff of a screenwriter’s dreams. With Harry Connick Jr., in the lead as the indefatigable Slamon and Bernadette Peters as Barbara Bradfield, the first woman whose life was saved by Herceptin, the film was guaranteed to attract some favorable attention. But, it also benefitted from an all-star cast behind the scenes, including Renée Zellweger as executive producer. The early funding difficulties, in Slamon’s judgment, delayed medical progress by as much as five to seven years. But, there is no doubt in his mind about Herceptin representing a paradigm shift in cancer treatment. With similar promising drugs already in use, and new ones in the pipeline targeting lung, prostate and other cancers, Slamon is confident that the future of this kind of research is secure. He foresees fundamental changes in the way a number of cancers will be treated just within the next four or five years. If he is right, and the success of Herceptin is matched for other malignancies, it will come, for a great many people the world over, as very good news indeed. Spring/Summer 2010 33