One of a small group of scientists who had a hand in developing Herceptin (trastuzumab) for the treatment of breast cancer, Dr. Debu Tripathy's current work is focused on understanding why some patients are resistant to the drug, and how to create more effective therapies for them.
Debu Tripathy, MD
When a friend died of leukemia during his childhood, Debu Tripathy was shocked. It was not the sort of thing he'd believed could happen to someone so young. But as Tripathy watched the way the girl's mother reacted to the loss, his disbelief turned to admiration.
"Her mother wrote a book and gave speeches advocating for some of the personal issues that people go through, how a family is drawn together in times of crisis," recalled Tripathy. "I was very moved by how she responded to her daughter's illness and death by doing something so positive."
More than 3 decades later, Tripathy, a world-renowned oncologist and translational researcher who fills several roles at the University of Southern California (USC), Los Angeles, remains deeply interested in the patient experience.
One of a small group of scientists who had a hand in developing Herceptin (trastuzumab) for the treatment of breast cancer, Tripathy's current work is focused on understanding why some patients are resistant to the drug, and how to create more effective therapies for them.
In part, he is accomplishing that by continuing his role as a lead investigator on the multi-institution I SPY trial. Through repeated biopsies of tumors from patients in the neoadjuvant setting, the trial's first phase correlated specific genetic profiles with drug resistance, helping to identify genes that could make good targets for future drugs. In phase II, women with breast cancer will receive the investigational drugs thought to best match the biology of their tumors.
True to what he learned from his friend's mother, Tripathy, 51, is just as committed to looking beyond laboratory and clinical research toward the holistic treatment of patients.
Early on, I became interested in the human side of cancer." ”
—Debu Tripathy, MD
"Early on, I became interested in the human side of cancer - how people make decisions, and the huge interest patients have in alternative and complementary medicine," Tripathy said. "We know, as physicians, that the amount of evidence [supporting such treatments] is very scant, yet people are very drawn and interested in it. I wanted to understand why that was and whether or not one could do meaningful research in that area."
About 10 years ago, that curiosity prompted Tripathy to test a group of Tibetan herbs for usefulness in cancer treatment, although the trial, starved for funding, did not move on to the next phase. A separate, promising trial involving the Chinese herb Ban Zhi Lian is expected to move forward.
Delving into the study of herbal medicines, especially before many targeted therapies had been developed, was an eye-opening experience that continues to inform Tripathy's work.
"Chinese and Tibetan treatments are personalized, but the typical scientific dogma has always been that you use the same treatment on everybody," he said. "It's interesting now because we see the whole field moving toward personalized medicine. Back then, it was different to think of doing a trial that way. I was trying to reconcile the notion of personalized medicine with doing well-done scientific trials, and that's still a dilemma we all face - how to take this evolving area and do individualized trials."
Center Takes Holistic Approach
At USC and its Norris Comprehensive Cancer Center, where he serves as co-leader of the Women's Cancer Program and as Art and Priscilla Ulene Chair in Women's Cancer, Tripathy is reasserting his interest in holistic treatment by helping to launch a Center for Integrative Medicine. Initially, the center will focus on the study of scientifically based approaches to nutrition and acupuncture.
Since joining the university in 2009, Tripathy also has helped start an oncology program that is focused on adolescents and young adults. "Many patients, especially those with a genetic disposition, get cancer in their late 20s or early 30s," Tripathy said, "and they have fertility preservation and employment issues."
In addition, Tripathy has nurtured the university's portfolio of clinical trials, expanding it to include potential therapies that target HER2-positive cancers, cyclin-dependent kinase inhibitors, or act as PARP inhibitors. At the same time, he has guided the institution in offering more educational opportunities to oncologists everywhere. In addition, he will serve as co-chair of the 29th Annual Miami Breast Cancer Conference, sponsored through Physicians' Education Resource (PER), scheduled for March 14-17, 2012, in Florida.
In his own lab, much of the work focuses on stem cell biology and other avenues toward inhibiting cancer cell growth. He also sees patients as part of the university's multidisciplinary breast cancer practice, and serves as a professor at the university's Keck School of Medicine.
It is a busy existence for Tripathy, who misses the chance to spend more time with his wife and 3 children, and to read books. But it is a labor he can't tear himself away from, given his boundless interest in his field.
"My greatest weakness is not being able to focus on two or four things that need attention," Tripathy said. "Many of us fall into the same trap - we get so excited about different projects that we want to help out and collaborate. One of my goals is to focus and prioritize things that can really move forward."
Early Lessons Influence Path
As a child, Tripathy was interested in both science and math. But his direction in life was shaped more by the influence of his parents.
His father, Kshetrabasi Tripathy, MD, moved his family from Pittsburgh, Pennsylvania, to South America in the 1960s. A professor at Tulane University's School of Tropical Medicine, he went to Cali, Colombia, to conduct research. Through his work, the elder Tripathy demonstrated that a protein malabsorption was a consequence of certain parasites, and discovered diets that helped patients recover from parasitic diseases, Tripathy recalled.
"He was really doing what we now call translational medicine - seeing patients and running a lab," Tripathy said. "Those early years with my father got me very interested in medicine."
It was his mother, though, who passed along Tripathy's interest in the human side of things - as well as his aptitude for playing the guitar and keyboards, taking pictures, and cooking.
"My mom is an artist," Tripathy said. "She started taking a lot of art courses and learning about regional art when we were in Colombia. Then, she was part of a group that opened a gallery, and she still is an active artist getting ready to open her own studio."
Tripathy was 12 when his family left Colombia to live in New Orleans. After attending high school there, he earned a bachelor of science degree in chemical engineering from the Massachusetts Institute of Technology, and then his medical degree from Duke University, where he went on to pursue his internship and residency. His fellowship, from 1988 to 1991, was in hematology and oncology at the University of California, San Francisco (UCSF).
Q: You’re doing some work with stem cells. Please explain.
A: We’ve just begun an exciting collaboration in the lab with a colleague, USC cancer biologist Parkash Gill, MD, who is interested in targeting stem cells. We’re developing a drug to work against the Notch receptor, a pathway involved in keeping stem cells in an immature form.
It’s been appreciated, in the last few years, that if you look at the malignant cells of a tumor, they are not identical. Some fraction appear to be stem cells that can give rise to a whole tumor. There is growing evidence that stem cells appear to be very resistant to chemotherapy, so when you’re treating someone, if they have a good response and their tumor almost disappears, the tumor cells left are the stem cells, and over time they may grow up and repopulate the tumor. If we can understand how stem cells are maintained in a stem cell state, and block or inhibit them and make them susceptible to medical therapies, this may step up the cure rate, especially in advanced cancers.
Dr. Gill has developed a variety of different antibodies to different targets involving stem cell pathways, and one target is the Notch receptor. He has developed an antibody now that can cause stem cells to mature or to die, so if combined with chemotherapy, one may be able to eradicate the whole tumor leaving no residual cells.
We want to understand what drug we should combine with stem cell inhibitors, and how to use that information and move it into the clinic, which we hope to do in a year and a half. We’ve submitted a grant with the aim of testing this concept and taking this into trials for patients with triple-negative breast cancer.
Q: Please discuss your recent efforts to understand more about resistance to Herceptin.
A: We’ve discovered some genes involved in resistance to Herceptin, and CXCR4 seems to be an important one.
We found it by looking at a gene array profile in a cell we made resistant to Herceptin in the lab. We looked at multiple genes in the cancer cell to see which seemed to be upregulated. We showed that knocking down certain genes recaptured sensitivity to Herceptin, and CXCR4 had the biggest effect. That was an exciting finding, because one of the hardest things in cancer is knowing what the best targets are.
A next step will be to take tissue from cancer patients and find out if CXCR4 is expressed more often than in Herceptin-resistant tumors. Then, we’ll attempt to develop a drug to inhibit CXCR4—an antibody or small-molecule inhibitor—since these agents are already in trials for other indications.
"When I was in medical school, the field that fascinated me most was immunology, the fact that the immune system could recognize bacteria and foreign bodies, that antibodies could be developed," Tripathy said.
Advancing HER2 Research
At Duke, he worked with Richard S. Metzgar, PhD, an immunologist whose lab was among the first to develop monoclonal antibodies, some of which could inhibit the growth of tumors in animals. Then, at UCSF, he worked with Christopher C. Benz, MD, whose lab was investigating the newly discovered HER2/neu gene - research that contributed to the development of Herceptin, a monoclonal antibody now approved for the treatment of HER2-positive breast cancer and metastatic gastric or gastroesophageal junction cancers.
"We were looking to turn off the gene using antisense DNA," Tripathy said. "We ran into a lot of technical problems, but we were finally able to turn off the gene. We showed that you can actually slow down the growth of breast cells."
Tripathy and his fellow researchers also discovered that several antibodies could shut down the growth of breast cancer cells. Eventually, they found themselves working in collaboration with a handful of groups across the country conducting similar research, including the lab of Dennis Slamon, MD, PhD, the first to discover that a mutation of the HER2 gene is expressed in about 25% of breast cancer patients, and, eventually, the leader of clinical trials of Herceptin.
"I was fortunate, so early in my career, to have worked in a lab with this antibody, to have done the trials, and to be presenting it in front of the FDA to get it approved," said Tripathy. "To go from the lab to the clinic so quickly was what got me involved and interested in breast cancer."
After finishing his fellowship, Tripathy stayed with UCSF for 11 years, ending his time there as an associate clinical professor of Medicine. He left in 2002, having been recruited by the University of Texas Southwestern Medical Center at Dallas to direct the Komen/UT Southwestern Breast Cancer Research Program and hold the Annette Simmons Distinguished Chair in Breast Cancer Research.
"My interest within the program was new potential therapies, many with HER2 targets," Tripathy said. "I was part of several research teams looking at molecular markers from tissue in patients getting treated with Herceptin to understand the drivers that made some people respond and some people resistant. In my lab, we discovered several genes involved in Herceptin resistance."
Prioritizing Patient Education
Between those efforts and the start of his work at USC, Tripathy took 2 years away from his research to turn his attention, once again, to the human side of cancer - in this case, communicating with physicians and patients.
The doctor served as president and CEO of PER, which is now based in Plainsboro, New Jersey, and is owned by an affiliate of Intellisphere, LLC. He also serves as editor-in-chief of CURE magazine, whose audience includes cancer patients, survivors, and caregivers.
Such activities mark a return to the values that helped spark his interest in medicine during his teenage years, Tripathy said.
In high school, Tripathy spent his summers working as a hospital orderly, and enjoyed speaking with patients about their experiences and trying to answer their questions.
"It struck me that, in general, patients were underinformed and physicians were so busy they didn't have time to explain," Tripathy recalled. "The idea of patients being able to empower themselves with knowledge to make better decisions was something that fascinated me."