By Mark Wheeler
Photos: Jessica Pons
It is roughly 2,500 miles from New Castle, Pennsylvania, to Los Angeles, California, but distance alone doesn’t define how far the two communities are apart. New Castle is a mill town that was known as the tinplate capital of the world in the early 1900s. L.A. is … L.A. Yet, UCLA’s Dennis J. Slamon, MD (FEL ’82), PhD, the 2019 recipient of the Lasker-DeBakey Clinical Medical Research Award — widely regarded as America’s top biomedical research honor — really hasn’t strayed far from his roots. His father, uncle and grandfather all were coal miners in West Virginia before Dr. Slamon’s parents moved to New Castle, where Dr. Slamon was born. Dr. Slamon choose to mine a different vein: data.
It is his belief in data and a dogged perseverance that led Dr. Slamon, professor and chief of hematology/oncology at the David Geffen School of Medicine at UCLA, to the groundbreaking development of the breast cancer drug Herceptin, a lifesaving monoclonal antibody for women with HER2-positive breast cancer, a particularly aggressive form of the disease. Monoclonal antibodies are proteins created in a lab that, when injected into humans, bind to and destroy specific invader organisms like cancer cells. He shares the award with H. Michael Shepard, PhD, an American cancer researcher then working at the biotechnology company Genentech, and Axel Ullrich, PhD, a German cancer researcher also formerly of Genentech and now at the Max Planck Institute of Biochemistry outside of Munich, Germany.
The Lasker Awards were established in 1942 by Albert and Mary Lasker to recognize researchers, clinical scientists and public servants who have made major advances in the understanding, diagnosis, treatment, cure or prevention of disease and to raise awareness of the ever-present need for research funding. They are known as the “American Nobel” — eighty-eight Lasker winners have gone on to be awarded Nobels. Dr. Slamon, who also is director of clinical and translational research at the UCLA Jonsson Comprehensive Cancer Center, is the second David Geffen School of Medicine scientist to win the award in the past two years; Michael Grunstein, PhD, Distinguished Professor Emeritus of biological chemistry, received the Albert Lasker Basic Medical Research Award in 2018 for his groundbreaking research on gene expression.
The key finding by Dr. Slamon and colleagues showed that the monoclonal antibody Herceptin binds to, and destroys, abnormal cells without harming nearby healthy tissue, much like a laser-guided missile hitting a select target. This was a major departure from then-common chemotherapies that Dr. Slamon refers to as the “hand grenade” approach, indiscriminately killing healthy as well as diseased cells. Proving that antibodies that bind to cancerous cells are an effective method for treating solid tumors transformed cancer care at a time, in the 1980s, when most cancer therapies were focused on excising tumors and developing better chemotherapies. The discovery opened up new research avenues, leading to multiple other targeted treatments that utilize antibodies to attack the disease at its genetic roots. Between 2.7 million and 3 million women have been treated with Herceptin, and women with HER2-positive breast cancer now have among the highest survival rates compared with all women with breast cancer.
Photo: Ellen Jaffe/Albert and Mary Lasker Foundation
MEDICINE CAPTURED DR. SLAMON’S ATTENTION EARLY IN HIS LIFE. As a child growing up in New Castle, he regularly was exposed to the doctors who treated him and his family. His father Joseph had quit coal mining, after surviving two mine cave-ins, only to lose his leg in a horrible car accident. So doctors making house calls were not infrequent visitors to the family’s home. The young Dr. Slamon was impressed by what he observed. “It made a big impact on me, even at a very young age,” he says. “They made people feel better, and I saw the respect my parents gave them. So I always thought it would make a pretty cool profession.”
That early idea lingered as Dr. Slamon came of age in a town where, culturally, education was not a big deal and sons usually followed their fathers into the mills or mines. But that would not be Dr. Slamon’s path. “There was no gravitational pull,” he says. “My parents never made me feel not to do something. They always told me if it is what I want, then I can do it.”
So Dr. Slamon focused on his education, and he excelled. “If something interested me, I would throw myself into it,” he says. It is an attribute that continues to this day. In high school, he developed a keen interest in biology, he says, and started to muse about his two interests — medicine and biology — and how to marry the two.
From there, it was a scholarship to Washington and Jefferson College, a small liberal arts school in nearby Washington, Pennsylvania. Dr. Slamon was the first in his family to go to college. He spent summers working in a steel mill to help pay for his education. The experience was clarifying: “It cemented that this wasn’t what I wanted to do with my life,” he says.
After graduation, he entertained multiple scholarship offers — West Virginia University, the University of Pittsburgh and the University of Chicago. He vacillated about the choice. “To show how naive I was at that time, I wasn’t sure where to go. Chicago was the best school, but it was a little intimidating; I had never spent time in a major city.” He sought advice from his college counselor, who looked at him like he was crazy. “’There shouldn’t be any choice,’ he told me. ‘Chicago. Go!’”
TO CHICAGO HE WENT, GRADUATING IN 1975 FROM ITS COMBINED MD/PHD PROGRAM. After completing his residency and chief residency in 1979, he accepted a fellowship to UCLA’s Department of Hematology-Oncology. It was not, Dr. Slamon acknowledges, the most obvious choice. UCLA today is a top-tier academic institution, with a medical school that is ranked No. 6 in the nation for research. But in the 1970s, it was still a “baby” among its peers, Dr. Slamon says. “UCLA graduated its first medical class in 1955; Harvard and Columbia graduated their first classes in the 1700s.” But that youthful energy is what attracted him to UCLA. “The place was still young,” he says. “It wasn’t ossified, and if you had some resources and a good idea, you could pursue it.”
Dr. Slamon hit the ground running, beginning his “marriage” of research and patient care. He became interested in a recently discovered class of genes called oncogenes. Oncogenes are mutated, but when healthy, they are “growth regulating” genes involved in normal cell growth. When mutations occur, though, they can cause a cell to grow out of control — cancer. With support from UCLA’s Jonsson Cancer Center Foundation and UCLA, he began to build a bank of human tumors — lung, colon, liver, breast — from physicians who had removed them from patients for therapeutic purposes. His collection may have been macabre, but Dr. Slamon believed that understanding the molecular composition of a tumor was key to understanding cancer’s origins. Most of his peers thought it was a waste of time — his application to the National Institutes of Health for a grant to fund the bank “essentially came back with a laugh track,” he says — arguing that it was hard enough to find a single mutation in a cancer cell in a petri dish; looking for one within the complex architecture of a tumor would be impossible.
But Dr. Slamon’s idea paid off. Knowing that most oncogenes are mutated forms of genes that regulate cell growth and division, he entered into a collaboration with Dr. Ullrich, who had isolated a number of growth regulating genes. As reported in the book Her-2: The Making of Herceptin, a Revolutionary Treatment for Breast Cancer, by
the Yale University developmental biologist and former NBC News science and health correspondent Robert Bazell, “Ullrich was at UCLA giving a seminar. Slamon took the opportunity to make a suggestion. He knew that Ullrich had genes for growth factors and receptors, the chemicals that carry grow-and-divide signals through the body. Slamon wanted to know which of these genes, if any, caused cancer. Slamon’s own collection of cancer tissues seemed like a natural place to look for links between Ullrich’s growth-factor genes and specific types of human cancer. Collaboration made sense. The two sealed a deal over a long dinner at a Thai restaurant in Santa Monica: Ullrich would send Slamon samples of DNA from his gene collection, and Slamon would try to match them to the DNA he had extracted from his tumor collection.”
There was little money at this early stage of his career, so Dr. Slamon hired a UCLA freshman, Wendy Levin, and taught her how to find matches between the oncogenes and the tumors. Now a physician, Dr. Levin is an oncologist in San Diego County, but while an undergraduate, she spent nights and weekends “sometimes sleeping on the floor in the lab,” she says, extracting DNA from tumors. It was tedious work, taking a piece of tumor tissue that had been frozen in liquid nitrogen, grinding it up, extracting the DNA and looking at one gene at a time for something awry. But the work bore fruit on a Saturday afternoon in June of 1986, when she found a match between the HER2 gene and a breast cancer tumor. “My heart started thumping,” Dr. Levin says. “It was a true eureka moment.” She excitedly called Dr. Slamon at home, offering to drive out to his house to show him the results. Dr. Slamon decided it would be OK to wait until Monday.
To read an interview with Dr. Dennis J. Slamon in the journal Cell about the development of Herceptin, to listen to an audio file of the interview:
THE GOAL NOW WAS TO FIND A WAY TO “FIX” THE HER2 ONCOGENE. “If we can understand what’s broken in a normal cell that makes it become a cancer cell,” Dr. Slamon says, “then we can develop smarter drugs that would only attack the cancer cells and leave healthy cells alone.” In other words, a guided missile as opposed to a hand grenade.
Dr. Slamon began testing monoclonal antibodies from different biotech companies and university labs. But it was while working with Dr. Ullrich that Dr. Slamon tested a monoclonal antibody developed at Genentech on cancer cells ultured in a petri dish. It was another eureka moment. When the monoclonal antibody was added to HER2 breast cancer cells, the cancerous cells stopped growing and dividing. When the researchers removed the antibody, the ancer began growing again. Just as remarkable, the antibody had no effect on other cells in the dish. That antibody was Herceptin.
At this point, Dr. Slamon had the data in hand to proceed to clinical trials. In 1987, he and Dr. Ullrich published their research in the prestigious peer-reviewed journal Science. Yet Genentech, which owned the rights to the drug, wanted no part of it. Having been burned by failures of earlier cancer drugs, the company had grown cautious. And Dr. Slamon still was a young researcher, without a track record. And, at that time, chemotherapy and cutting still were the gold standards.
There was a core group of Genentech scientists, led by Dr. Shepard, who believed in Drs. Slamon and Ullrich’s science, but It took years of cajoling and outright arguing to advance the cause with Genentech’s executives. Frustrated, Dr. Ullrich left for Germany. Dr. Slamon would fly from Los Angeles to San Francisco at every opportunity to buttonhole Genentech executives and press reams of data into their hands. “There was a lot of eye rolling. They called me Dennis the Menace,” he says. “Looking back, a small part of me is sympathetic to those decision-makers. Clinical trials are enormously expensive and time-consuming. If you go out on a limb and fight for one and it fails, that’s a career ender.”
Still, it was maddeningly frustrating for Dr. Slamon. “I would sit in the conference room and roll out the data. ‘Here it is, here’s the proof, it works,’ I’d tell them. And they’d still say no.”
It was 1989. The only bright spot during this period was an infusion of research dollars that flowed from the intercession of an appreciative family. Lilly Tartikoff, the wife of Brandon Tartikoff, then the president of NBC, was grateful for the care that Dr. Slamon had provided to her husband during his fight against Hodgkin’s disease — randon Tartikoff died in 1997 — and she went to Ronald Perelman, the owner of the cosmetics company Revlon, and urged him to support Dr. Slamon’s research. “He’s Frankenstein and I’m the monster,” Lilly Tartikoff joked in an article about the development of Herceptin published in UCLA Magazine in 1998. “Together, there’s no stopping us.”
Tartikoff brought Dr. Slamon and his colleague John A. Glaspy, MD ’79, a Jonsson Comprehensive Cancer Center scientist who today is the Estelle, Abe, and Marjorie Sanders Endowed Chair in Cancer Research and director of the center’s clinical research unit and the Women’s Cancer Research Program, to make a pitch. Step-by-step, Dr. Slamon
laid out his HER2 findings to Perelman’s representative, Jim Conroy. Dr. Glaspy’s pitch was more blunt. It could take two-to-three years to receive funding from the government to advance the research, he said, and in that time “you’ve got a Rose Bowl full of women dead from breast cancer.”
In response, Perleman and Revlon came on board with a $2.4 million gift over three years. “It would have taken four concurrent National Cancer Institute grants to build the equivalent of the program Revlon funded with just the stroke of a pen,” Dr. Slamon said in the UCLA Magazine article. “And there was no writing a grant, submitting it, waiting eight-to-12 months to hear. This gift allowed us to follow our leads almost instantaneously and made a huge difference in this whole story.”
Now with substantial funding in hand, Dr. Slamon moved full-steam-ahead with his HER2 research. He was able to conduct the first small study in humans, using the mouse version of the antibody, proving it safe, and in lab work found that adding the chemotherapy drug cisplatin to the antibody enhanced its effects.
Finally, in 1992, Genentech agreed to support a Phase I clinical trial, which is designed to test the safety and side effects of a new drug. Dr. Slamon recruited 15 women for the study. “All of us had been told we have Stage IV cancer, and all of us were told we were going to die,” says Barbara Bradfield, a participant in the trial.
With nothing to lose, the women agreed to participate in the trial, hoping it would help them, and, if nothing else, help future women with breast cancer. Still, Bradfield had to be persuaded. “I was done with chemotherapy (the trial involved Herceptin combined with the chemotherapy drug cisplatin), and when [Dr. Slamon] first called, I refused. But he called back the very next morning and gently persuaded me to reconsider. He has a way about him that is both compassionate and passionate in his belief about his research.”
Only five of the women were able to complete the trial. Bradfield, the sole remaining survivor of the group, now is a touchstone in the history of cancer research and therapy; at the trial’s conclusion, Bradfield, who was 49 when she started the trial and now is 77, had gone from a diagnosis of Stage IV cancer to being cancer free.
“Patient care is gratifying,” Dr. Slamon says. “But if that was all I did day in and day out, I would find it frustrating. Because there’s only so many tools we have. That’s why being able to participate in something new, the research, is so important to me. It gives all of us hope.”
The results of the Phase I trial were enough to convince Genentech and the FDA to proceed with the larger Phase II and Phase III trials. Herceptin, finally, received its initial FDA approval in 1998.
THE SUCCESS OF HERCEPTIN HAS BEEN NOTHING SHORT OF REMARKABLE. In the early 1990s, women with the HER2+ subtype had an average life expectancy after diagnosis of three-to-five years. Today, women with the HER2+ type of breast cancer now have among the best prognoses of women with breast cancer. Dr. Slamon’s research has shown that Herceptin increases the amount of time that patients live after their diagnoses by more than 50 percent. Depending on the stage of diagnosis, women with the HER2+ subtype now average seven-to-10 years of disease-free survival. In total, an estimated 2.7 million to 3 million women around the world have been treated with the drug. “Every time now, when I inject Herceptin into a patient, I still get chills down my spine thinking about how far we’ve come,” says Dr. Levin, Dr. Slamon’s former freshman assistant.
Now 71 years old, Dr. Slamon has no plans to retire. “Not until they throw me out,” he says, smiling. “The great thing about UCLA is working with great people who keep it fresh. I have 25 people in my lab now, and they bring new ideas and approaches all the time, and they keep me as challenged as I’ve ever been.”
Dr. Slamon notes there were sacrifices that he had to make, especially with his family. “I missed things that I today regret,” he says. “My wife Donna should have turned me out years ago. I missed a lot of things with my kids, although Donna always explained to them what I was working on.” Dr. Slamon has two grown children; one does market research for Major League Baseball and the other has a successful writing career in the entertainment business.
But Dr. Slamon says that his sacrifice was nothing compared to that of his patients, especially the ones who agreed, without much hope, to participate in the trials. He holds particular fondness for Bradfield and the 14 other women who were part of the Phase I trial. “Those patients who entered the Phase I trials are not research subjects or patients, they’re colleagues,” he says. “They are every bit as much of the story as anyone else who is involved because they participated in a trial knowing that we might be giving them something that could hurt them, and because it was a safety test we had to start at levels that were not likely to even help them. But they all agreed and volunteered with the attitude that while it may not directly help them, it might help the next woman behind them.”
Dr. Slamon is grateful for the recognition he and his colleagues have received from the Lasker Foundation. But there’s another prize for which he is grateful, too. Melody Cobleigh, MD, an onocologist at Rush-Presbyterian-St. Luke’s Medical Center in Chicago, had helped to recruit patients for the Phase III trial. At its conclusion, she asked her patients to write a note to Dr. Slamon, telling him how Herceptin had affected their lives. Dr. Slamon keeps the 17 notes he received from the women, and to this day they still move him.
To read an interview with Dr. Dennis J. Slamon in the journal Cell about the development of Herceptin, to listen to an audio file of the interview and to view a video of Dr. Slamon’s acceptance remarks, click on the link to this article at: uclahealth.org/u-magazine
Mark Wheeler is a freelance science writer in Los Angeles and a former writer and editor for Discover magazine and senior media relations officer for UCLA Health.