Murray Korc: Putting Principles into Practice
"There is a principle," he says. "You have a basic science discovery, and you then test it out in a number of model systems, including cell models and mouse models." The most promising drugs make their way into clinical trials in humans. If all goes well, what begins as a research project can end up improving patients' lives.
Korc has put this principle to work throughout his career. He studies pancreatic cancer, a particularly difficult disease to treat. If the cancer is spotted soon enough, surgical removal of the tumor can result in long-term survival. But because the cancer begins to spread to other parts of the body so early in its development, only 20 percent of patients are good candidates for surgery. As a result, most patients survive six months or less, and only five percent live longer than five years.
Despite these statistics, Korc's faith in biomedical research and his general outlook on life—"I'm naturally optimistic," he says—have helped him remain positive. That optimism is beginning to pay off. After more than 20 years as a leader in pancreatic cancer research, Korc's efforts have recently resulted in a number of clinical trials.
Laying the Groundwork
For Korc, the process of going from basic science to medical advances began in 1977 in a lab at the University of California at San Francisco. Having already earned his medical degree, Korc was at UCSF on a fellowship to train as an endocrinologist, but he found himself fascinated by research. His colleagues advised him to focus on clinical care or on research, but Korc was reluctant to give up either. After completing his fellowship, Korc moved to the University of Arizona, where he saw patients and ran a lab that investigated type 2 diabetes and the effects of insulin.
In 1984, Korc came across some old articles linking type 2 diabetes and pancreatic cancer, and was inspired to find out what was known about pancreatic cancer. When he realized that no one was investigating the factors involved in the growth of pancreatic cancer, Korc decided to look into it himself.
Before long, Korc figured out part of the connection between pancreatic cancer and diabetes. He discovered that insulin, which is produced by the pancreas, can stimulate pancreatic tumor growth. He also found that a molecule called epidermal growth factor receptor (EGFR), which is located on the surface of some cells, binds with a protein called epidermal growth factor (EGF), leading to cell division. Korc showed that an overabundance of EGFR caused cells to divide rapidly and to be invasive, meaning that high levels of EGFR might be another factor in the uncontrolled cell division that leads to a tumor and its ability to metastasize.
The next step came when Korc examined EGFR in tumor samples surgically removed from patients with pancreatic cancer. In patient samples that contained a lot of EGFR and a protein called TGF-alpha (transforming growth factor alpha), the cancer was likely to return quickly, even when the surgery had gone well. Patients with less EGFR in their samples were more likely to survive longer, for at least three years. These results confirmed the importance of EGFR-and raised the hope that blocking this molecule might make it possible to slow the cancer's progress.
Research on Trial
In 2005, the Food and Drug Administration approved the use of a drug, erlotinib, that works by disabling EGFR, following the path laid out by Korc's work on EGFR. Erlotinib is now regularly administered to patients with advanced pancreatic cancer, combined with a standard chemotherapy treatment called gemcitabine. The combination has been shown to prolong life slightly.
Hoping for further improvements, J. Marc Pipas, MD, medical director of the Cancer Center's Gastrointestinal Oncology Program, is starting a Phase I clinical trial that will test the effectiveness of erlotinib and gemcitabine in combination with the drug FG-3019, which targets another pancreatic cancer growth factor. As with erlotinib, Pipas says, FG-3019 was developed in part thanks to work done by Korc. Dartmouth is one of only two sites nationally using this combination, and Pipas says the trial promises to be "very exciting." Korc, who serves as chair of the Department of Medicine as well as scientific director of the Pancreas Cancer Program, says that one of Dartmouth's strengths is the ability of its faculty to collaborate in all stages of the development of new treatments. Pipas recently completed a related Phase II clinical trial that grew out of Korc's research on EGFR. Patients were given radiation therapy, gemcitabine, and the drug cetuximab, another EGFR inhibitor, before undergoing surgery to remove the tumor. Final results are not yet available, but Pipas says that the early signs are very promising, including cases where no tumor remained by the time surgery was performed. He hopes to continue with a Phase III trial.
A Pioneer's Progress
A third clinical trial currently underway is the product of Korc's research into another aspect of cancer progression-angiogenesis. In order for tumors to grow beyond a certain size, they require oxygen and nutrients, just as normal cells do. To get those essentials, cancer cells recruit nearby tissues to create new blood vessels-a process called angiogenesis.
Putting Principles into Practice
One important molecule involved in angiogenesis is vascular endothelial growth factor (VEGF). Cancer cells secrete VEGF into surrounding tissues, where it tells other cells to start building new blood vessels. In one study, Korc examined whether blocking this process would decrease tumor growth. Mice were injected with cancer cells. Then, two days later, some of the mice were given a drug, called VEGF Trap, which soaks up VEGF, preventing it from interacting with other cells.
After two weeks of treatment, there was a noticeable difference between the two groups. In the mice given VEGF Trap, the drug had blocked at least 89% of the tumor growth compared with the cancer's progression in mice that did not receive the treatment.
It's still too early to tell how effective this method might be in humans, but Dr. Pipas is working on a Phase I trial to find out. It's another example, he says, of the importance of Korc's research. "He's really a leader in pancreatic cancer," says Pipas.
The National Cancer Institute (NCI) seems to agree. Just this fall, the NCI provided Korc with a MERIT Award, a prestigious funding opportunity that is both a recognition of all that Korc has accomplished and a sign that further breakthroughs are yet to come. It's also proof that he was wise not to heed the advice he was given decades ago to limit his interests to clinical care or research.
And, as always, Korc remains optimistic, despite the many obstacles involved in studying pancreatic cancer. "We need to do better," he says, "but we've made a lot of progress."
January 10, 2009
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