Found in Translation: Deliberate Approach Transforms Discovery Into Treatment Advances
July 15, 2008
By Dagny Stuart (from the Spring 08 Momentum)
Sometimes an accident can be a good thing. Sometimes an accident saves lives.
Just ask Teresa Lundberg, a Mt. Juliet, Tenn., cancer survivor who believes her life was saved because her breast cancer was treated with a drug called Herceptin.
“My mom dying of lung cancer was my last experience with cancer,” explained Lundberg. “Through the grace of God I was urged to get a second opinion. Dr. Mark Kelley and Vanderbilt-Ingram Cancer Center were highly recommended through various sources. Then I was blessed to be assigned to Dr. David Johnson and Dr. Julie Means, my oncologists. They said my tumor was HER2 positive, which meant there was something that was telling it to grow at a faster rate. I wanted to do whatever I could to stop it, and they gave me hope that that could be accomplished.”
Stopping the tumor’s growth was possible because of a series of happy accidents in the laboratory years earlier that revealed why tumors grow, and led to the development of drugs to halt that growth. Nobel Laureate Stanley Cohen, Ph.D., Vanderbilt distinguished professor of Biochemistry Emeritus, started the chain of discovery – and translation of that discovery – that led to the development of Herceptin.
Cohen, along with Viktor Hamburger, Ph.D., of Washington University, and Italian scientist Rita Levi-Montalcini, Ph.D., was investigating nerve growth in chick embryos in the early 1960s. They injected the embryos with an extract from snake venom, thinking that it would stop nerve growth. Instead they were amazed to see an array of new nerve fibers. Eventually, Cohen tried injecting related extracts into baby mice. Not only did the nerves grow, Cohen noticed something equally remarkable. The baby mice opened their eyes several days earlier than normal. The extract was making skin cells grow faster, allowing the eyes to open early. The same thing happened with human skin cells.
Cohen realized immediately that he had stumbled on something revolutionary. “There are very few ways you can improve on nature and make it go faster,” he explained. Eventually Cohen isolated a protein that made the baby mice open their eyes early. It was named epidermal growth factor or EGF because it makes the epidermis or top layer of skin grow.
What started as an interesting theoretical exercise resulted in Cohen’s “aha” moment, and it launched decades of research by cancer scientists who realized that EGF plays a role in cell growth, including cancer cells. Since cancer is the result of uncontrolled cell growth, finding a way to block that growth is key to treating the disease.
By the 1980s other scientists investigating brain tumors in rats found that a nearly identical cancer-causing gene (oncogene) existed in humans and was present in excessive amounts in about 20 percent of breast cancers. The product of that gene was a receptor that was firing signals for cancer cell growth. Once found, investigators finally had a target for breast cancer – the HER2 receptor. They immediately focused on developing a drug that could block the HER2 receptor. Herceptin is that drug and it is saving the lives of some women whose breast cancer is positive for the HER2 receptor.
Teresa Lundberg was one of the patients enrolled in one of the clinical trials that proved Herceptin could make a difference. “I felt it was another avenue out there to help my chances,” she said. “I didn’t want to sit back and feel that I had not done everything I could to go after this cancer.”
Halfway through that trial, researchers determined Herceptin was showing such strong results it became part of the standard treatment regimen for every woman in the trial. Today, oncologists routinely test breast cancer patients to find out if their tumor is positive for the HER2 receptor. The test not only identifies women who should benefit from the drug, it prevents women who are negative for the HER2 receptor from being exposed to a therapy that is unlikely to work.
“We wouldn’t have these treatments if somebody hadn’t been working in the lab,” said Lynn Matrisian, Ph.D., professor and chair of the Department of Cancer Biology. “I don’t know if people understand how much time, thought and effort, and trial and error, go into figuring out which discoveries are going to be translated.”
‘We are less in the dark this way’
While serendipity will always play a role in biomedical discovery, translational research is a deliberate approach to transform scientific discoveries from the laboratory into clinical applications for patients – and to take information from the clinic or patient bedside back to the laboratory for exploration.
“Translational research is mechanism-based research that is applicable to patient care,” explained Carlos L. Arteaga, M.D., professor of Medicine and Cancer Biology, and director of Vanderbilt-Ingram’s Breast Cancer Specialized Programs of Research Excellence (SPORE) grant funded by the National Cancer Institute. “We now have biomarkers or targets that we are identifying in tumors, and we have developed drugs to hit those targets. Since we know what the drug hits and we know how it works, we are in a position to understand why it doesn’t work in some cases. We are less in the dark when we do things that way and can provide more information so patients and their doctors can make a more informed decision.”
This search for biomarkers identified in the laboratory produced another new drug, Gleevec, which is showing significant results in many patients with chronic myeloid leukemia. This blood disease occurs when pieces of two chromosomes break off and swap places on the opposite chromosome. This chromosome mix-up causes a blood cell protein to be turned on all of the time, telling the bone marrow to make too many abnormal white blood cells. Gleevec blocks that signal.
“Gleevec is a beautiful example of a targeted therapy and it got everyone in the cancer field excited,” according to Matrisian. “It is a drug designed to interact with a specific protein that in essence drives the cancer. If you stop that protein you stop the cancer.”
Matrisian is one of the Vanderbilt-Ingram researchers devoted to advancing translational research so patients benefit more quickly from discoveries in the laboratory. She is now taking her expertise to Washington, D.C., where she has been appointed to a leadership post with the National Cancer Institute’s Translational Research Group. For the next two years she will spend half of her time at NCI headquarters, spearheading the effort to streamline the government’s oversight and funding of translational research.
Vanderbilt-Ingram now ranks seventh in the nation in research funding from the NCI, receiving 147 grants of more than $66 million in fiscal year 2007. This includes three SPORE grants (in lung, breast and gastrointestinal cancer) and other “team science” grants designed to facilitate the interaction and collaboration required to make scientific translation happen more deliberately and more quickly. In fact, to be successfully funded, SPOREs must focus on translational research that links knowledge of human biology to develop and test interventions in patients.
“It is absolutely critical to have an environment in which a variety of individuals work well together as a team – basic researchers, physician-scientists and physicians who focus on patient,” said Jennifer Pietenpol, Ph.D., director of Vanderbilt-Ingram. “The SPOREs, for example, include investigators in 10 or 12 different academic departments and divisions, all bringing their perspective, knowledge and skills to bear. The growth in our funding is a tribute to our approach to team science and our focus on how we can impact patients.”
One focus of Pietenpol’s own NCI-funded research is to find biomarkers for a type of breast cancer whose causes remain a mystery. These so-called “triple negative” breast cancers are negative for estrogen and progesterone receptor expression and HER2 gene amplification. While they have a distinct gene expression profile, they do not respond to commonly used chemotherapy drugs. Pietenpol, Ingrid Mayer, M.D., Josh Bauer, Ph.D., and Jennifer Rosenbluth are trying to find the clues that will tell them what is driving cancer growth in those tumors. If they can find those targets in the laboratory, they may be able to identify combinations of drugs or targeted therapies that can effectively stop or slow the cancer’s growth.
While the mechanisms for some types of cancer are still hidden in the maelstrom of human biology, researchers say the mist is beginning to clear and it’s happening quickly.
“It’s important for people to know that the gap between what we understand about cancer and what we can do about cancer has significantly narrowed in the last 10 years,” explained Robert Coffey Jr., M.D., professor of Cell and Developmental Biology and co-director of the Vanderbilt-Ingram GI SPORE grant from NCI. The GI SPORE is focused on colorectal cancer research. An estimated 153,760 patients were diagnosed with colon and rectal cancer in the United States in 2007 with 52,180 deaths, according to the NCI.
Coffey and GI SPORE co-director Mace Rothenberg, M.D., professor of Medicine, are utilizing the Vanderbilt imaging center to look at what happens to cells when they are hit with targeted agents.
“We have been able to non-invasively image cell proliferation, cell death or apoptosis and EGF receptor levels in mouse tumors, and we can do it in real time,” said Coffey. “We’re hoping to advance these imaging capabilities into human trials so we can determine whether a patient has responded to a treatment. This would eliminate the need for invasive tumor biopsies.”
Coffey says far too few patients are signing up for the clinical trials that could determine how well some of the new targeted agents work. Those clinical trials have helped accelerate the pace of translational research.
Patients play a pivotal role
After her experience in the Herceptin test, Teresa Lundberg has become an advocate for clinical trials.
“To this day, if there were a trial I was a candidate for, I’d be the first to raise my hand because I’ve seen so much good come from these trials,” she said.
Lundberg credits support from family and friends and the resources and support at the cancer center for her positive experience.
“The staff in the infusion room are walking angels,” said Lundberg. “Then there was Pam Carney, the clinical trials nurse who helped coordinate my care. Pam was absolutely my guardian angel because I didn’t have to worry about making appointments, when to get my blood work done and where I was supposed to be. She was my relaxing soul.”
Lundberg says she now recommends that other adults consider clinical trials.
Patients also contribute to scientific discovery when researchers are allowed to study tissue and blood samples obtained during biopsies and surgeries. As scientists develop new theories, it’s crucial for them to test those ideas by studying human samples to search for blood and tumor biomarkers.
Vanderbilt has created a massive DNA databank with as many as 50,000 DNA samples obtained from blood specimens by late 2008. The Ayers Institute for Pre-Cancer Detection and Diagnosis at Vanderbilt-Ingram is building another repository for colon polyps. Because colon polyps often become cancerous, this database of tissue samples is helping researchers gain insights into what causes polyps and whether they are likely to recur. One of the goals of the Ayers Institute is to create a blood test that would predict colon cancer.
A blood test to predict or confirm the presence of cancer is the scientific community’s magic quest. While researchers are moving forward on this quest, the prize has proved to be elusive. David Carbone, M.D., Ph.D., professor of Medicine and co-director of the Vanderbilt-Ingram Lung Cancer SPORE, is focused on developing such a blood test for lung cancer because it is the most common cancer without an approved screening and early detection test. Far too many lung cancer patients aren’t diagnosed until the disease is advanced, and this delayed diagnosis is just one of the reasons only 15 percent of people diagnosed with lung cancer are alive five years later.
“The most common imaging tests simply tell us there is something suspicious in one of the nodes in the lung,” explained Carbone. “We have to do an invasive test to find out if the tissue is cancerous. We believe there is a better way to get the answer by looking at proteins in the blood that could serve as biomarkers for lung cancer.”
This search for biological targets is the hallmark of today’s cancer research, and since each cancer patient’s biological signature is different, scientists say treatments are becoming much more individualized.
“The challenge is how to rationally combine multiple drugs for the right patient,” according to Carlos Arteaga. “We’re trying to determine how to predict, based on the genetic makeup of the tumor at the time of diagnosis, what would be the two or three combinations that would be rational for that patient and that will be well-tolerated and affordable. Those are big questions and the essence of personalized medicine. That’s a major frontier.”
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