Trailblazer C. Bart Rountree, M.D., provides hope for liver cancer patients
According to the World Health Organization, hepatocellular carcinoma (HCC), commonly referred to as liver cancer, ranks third behind lung and stomach cancers in numbers of cancer deaths worldwide. Liver cancer is also one of the few cancers that are on the rise in the United States. Although the liver has the ability to completely regenerate itself during short-term injury, once cancer appears, prognosis for recovery in adults is not good. Researchers led by C. Bart Rountree, M.D., at the College of Medicine, seek to extend the lives of adults who suffer from liver cancer by providing personalized, targeted therapies based on manipulation of liver proteins CD-133 and c-Met. These proteins are found on the surface of stem cells and cancer stem cells in the liver.
“The five-year survival rate of HCC patients is only 5 percent when diagnosed after metastasis. Sorafenib, the only approved medication for advanced HCC, benefits patients with an extra two months survival,” said Rountree. “We aim to use our research findings to design smarter therapies for the patients with advanced disease and provide hope for better care.”
Rountree is an assistant professor of pediatrics at the College of Medicine with a joint appointment in the Department of Pharmacology. His areas of expertise are hepatology, nutrition, and pediatric gastroenterology. Rountree’s educational background includes a medical degree from the University of Texas at San Antonio and a residency and fellowship at the Children’s Hospital of Los Angeles. His current research interest is not where he started. His research focus began to change in 2003, when Rountree was given the opportunity to conduct embryonic stem cell research while serving as a pediatric gastroenterology fellow in Los Angeles. His initial objective was to cure liver disease in children by using stem cells. After about two years of work, he discovered that there may be a link between liver stem cells and cancer during chronic liver injury. He decided that—using the proposed stem cell-based therapies—he would be unable to surpass the more than 90 percent success rate of liver transplants in children, so he chose to pursue further his stem cell research to find alternative HCC therapies.
Among the various collaborators on his CD-133 and c-Met research, Rountree is working with College of Medicine colleagues Wei Ding, M.D., Ph.D., and Hanning You, Ph.D. Ding, a research associate, is credited with linking the c-Met receptor/signaling protein to metastatic disease in HCC. You, a post-doctoral fellow, has been investigating the surface protein CD-133, which is a cancer stem cell marker. On the basic scientific aspects of the research, Rountree and his colleagues collaborate with Shelly Lu, M.D., and Bangyan Stiles, Ph.D., both from the University of Southern California’s Keck School of Medicine; as well as Kasper Wang, M.D., from the Children’s Hospital of Los Angeles. CD-133 is an epithelial cancer stem cell. Within models of liver cancer, Rountree and his team identified these cells before development of a primary tumor. The CD-133 research seeks to specifically target and treat potentially malignant CD-133 stem cells and prevent liver cancer before it begins.
Stem cells are the “factories” of tissues and organs in that they can replace injured tissue. One of the hallmarks of stem cells is their ability to resist cell death. This theory has been applied to the field of cancer stem cells, which resist chemotherapy. After a tumor is treated with chemotherapy, the resistant cancer stem cells remain and regenerate the carcinoma. The team is trying to find out why these cancer stem cells survive. Building on previous models of adult chronic liver injury, Rountree and his team are using mice and applying an inhibitor to those whose tumors express. By targeting the c-Met protein, tumor growth and proliferation was suppressed. Team members hypothesize that such personalized treatment will improve the outlook for the 45 percent of liver cancer patients with c-Met+ tumors, which is associated with a very poor prognosis. By specifically targeting therapy to the cancer stem cells, researchers anticipate destroying these cells, which are the most malignant, to allow traditional chemotherapy to treat the remaining tumor. Roundtree expects that inhibiting c-Met will not only prevent tumor regrowth within the liver, but also inhibit the cancer from metastasizing in other parts of the body. The goal of these efforts is to use therapy targeting only stem cells in concert with chemotherapy.
“The breast cancer field made a very interesting discovery a few years ago, when researchers found a linkage between cancer stem cells and metastasis, known as Epithelial-to-Mesenchymal Transition (EMT),” said Rountree. The team recently discovered that during EMT in liver cancer, the cancer cells—through increased c-Met signaling—acquire the ability to spread from the liver to other parts of the body.
Although the research is in its early stages and promising, Rountree’s team is working with Yixing Jiang, M.D., Ph.D., from the Division of Hematology/Oncology to apply to participate in a trial using a c-Met inhibitor for advanced liver cancer. “So far, we have had some exciting findings in our early testing, and hope to move these findings to the clinic in the very near future,” Rountree said.
The research team’s efforts continue to be funded by the American Cancer Society Research Scholar Award, Barsumian Trust, Children’s Miracle Network, National Institutes of Health K08 and R03 series awards, and the Penn State Clinical and Translational Science Institute.
– By Alicia E. Riegel-Kanth, M.P.A.