Robert Coffey Jr., MD, Anne Powell, PhD, and their colleagues at Vanderbilt-Ingram Cancer Center have identified a new population of stem cells that may help better understand colorectal cancer and how it grows. Photo courtesy of Vanderbilt.
Discovery May Advance Cancer Therapy
What makes some stem cell populations multiply rapidly while others are laggards? And what would the answer to this question tell scientists working to understand colorectal cancer, the second leading cause of cancer death in the United States?
Much of Vanderbilt-Ingram’s colorectal research today is built on a foundation laid decades ago by Stanley Cohen, PhD, a Vanderbilt biochemist who received a Nobel Prize in 1986 for his discovery and characterization of epidermal growth factor and its receptor. Today, Cohen is retired and lives in Nashville.
Research ongoing in the Vanderbilt-Ingram Cancer Center laboratory of Robert Coffey Jr., MD, is tackling that mystery, and a recent advance there puts scientists yet another step closer to improved colon cancer therapies. As reported this spring in the journal Cell, Coffey and his colleagues have identified a new population of stem cells, and these cells are unlike any other identified in the colon. They’re slow growers, what scientists describe as “quiescent,” while other stem cell populations in the colon are proliferating much more rapidly.
Coffey said there’s been a “rethinking” about cancer from a stem cell perspective – and a recognition that while conventional therapies may eliminate 90 percent of a tumor, it can still “come back with a vengeance,” repopulated by the cancer’s stem cells. A promising therapy for treatment of colon cancer would be to target these colon cancer stem cells.
The stem cell population identified by Coffey and colleagues negatively regulates the epidermal growth factor (EGF) receptor by accelerating its degradation within the cell. “After we fully characterize this population of normal colonic stem cells, the next step will be to determine how this population of stem cells relates to colon cancer stem cells,” Coffey explained.
To that end, researchers in Coffey’s lab have been able to genetically manipulate this new population of stem cells to cause colon tumors in a laboratory mouse. “What that shows us is that this population has the ability to cause tumors under the right conditions. Now the question is, how is this relevant to human disease? Now we have an additional aspect to examine in human tumor formation,” said postdoctoral fellow Anne Powell, PhD, the first author of the Cell paper.
This work is part of Vanderbilt’s Gastrointestinal Special Program of Research Excellence, an initiative sponsored by the National Cancer Institute. The NCI established SPOREs in 1992 to promote interdisciplinary research into specific cancer types. The emphasis is on translational projects, work that spans the gap from basic laboratory discovery to clinical application. Vanderbilt nabbed its first highly competitive GI SPORE grant of $13 million in 2002, under the direction of Coffey. In 2007, that grant was renewed for another five years with $11.8 million, and Vanderbilt received the top score in the country in that pool of applications. Funding of the 2012 renewal application is pending, although Vanderbilt’s application was scored, yet again, among the top in the country. The decision on funding has been delayed more than four months because the NCI budget has not been approved.
“Our GI SPORE is focused exclusively on colorectal cancer, and we have some very exciting developments in terms of innovative diagnostic and therapeutic approaches to colorectal cancer,” Coffey said.
In the area of drug development, SPORE funds have allowed Vanderbilt researchers to develop a novel inhibitor of Wnt signaling, a pathway that is thought to be overactive in more than 80 percent of colon cancers. This therapy is now being tested in mice.
Yet another SPORE project focuses on promising candidate compounds that will inhibit a specific mutation called KRAS, which is present in about 50 percent of colon cancers and more than 90 percent of pancreatic cancers. A clinical trial is also under way at Vanderbilt to help understand why patients with mutant KRAS aren’t helped by the drug Cetuximab, which blocks the EGF receptor and has been approved by the federal Food and Drug Administration. “Unfortunately, it only is successful in about 10 percent of patients, and the results are not long-lived. This underscores the need for new approaches to the treatment of colorectal cancer,” said Coffey, adding, “What makes our study particularly exciting is that we’ve identified this new population of normal colonic stem cells that are largely quiescent. This population is actually marked by a negative regulator of the EGF receptor, which may help put the brakes on cell growth and proliferation.”
Coffey’s lab consists of a team of 16 individuals, ranging from undergraduate and graduate students to technicians and postdoctoral and senior research fellows.