Cancer Biology, Genetics
The Johns Hopkins University
Dr. Vogelstein is also Clayton Professor of Oncology and Pathology and director of the Ludwig Center for Cancer Genetics and Therapeutics at the Sidney Kimmel Comprehensive Cancer Center of the Johns Hopkins University School of Medicine.
The Molecular Basis of Colorectal Cancer and Its Implications for Patients
Cancer represents a cellular insurrection. Tumors form when a renegade cell accumulates mutations that allow it to reproduce without restraint and defy the molecular signals that tell it to stop. Over the past two decades, Bert Vogelstein and his team have uncovered the specific genes and mutations responsible for colorectal cancer and established a genetic model for cancer progression that has enhanced our understanding of the formation and development of all cancers. They are now using this knowledge to develop diagnostic tests for identifying individuals at risk for developing colon cancer and to search for new treatments for the disease.
Although he majored in math as an undergraduate, Vogelstein chose to pursue a medical degree so that he could focus on problems in human health. One of his first patients was a four-year-old with leukemia. "Here was this little girl with a disease that we knew almost nothing about," he says. "It was very frustrating." That feeling of helplessness drove Vogelstein to the lab, where he hoped he could make sense of cancer.
To get a handle on the molecular changes that drive malignancy, Vogelstein turned to studies of colorectal cancer. He chose this cancer, in part, because various forms of colorectal tumors can be obtained for genetic analysis. Vogelstein hoped to find evidence that colon cancers can be caused by the loss of a tumor suppressor, a gene that in normal cells acts as a molecular brake to control division. Tumor suppressors were high on the list of suspects because cancer cells frequently contain chromosomes that are broken or missing large chunks. These deleted regions, Vogelstein thought, were likely to harbor genes that normally restrict cell proliferation. The problem was that, at that point in time, tumor-suppressor genes were hypothetical; no one had yet identified a particular example.
Surprisingly, Vogelstein's first search turned up TP53, a gene that had not been known to be altered in cancers and was thought to work in an opposite fashion from a tumor-suppressor gene, stimulating rather than inhibiting growth. But Vogelstein and his students provided incontrovertible evidence that TP53 really was the tumor-suppressor gene on chromosome 17 that they had been searching for. In colon cancer cells, both copies of TP53 were disabled; if one copy had been deleted, the other always harbored an inactivating mutation. They subsequently found that TP53 was involved not only in colon cancers, but in most types of human cancer, suggesting that the gene might be a common denominator for human cancers. This stimulated a revolution in cancer research: more than 20,000 mutations of TP53 have been identified in human cancers since Vogelstein's first report.
Vogelstein then joined forces with Kenneth Kinzler, who started out as a graduate student in Vogelstein's lab and is now a professor at Johns Hopkins. Working together, the researchers identified additional genes involved in colon cancers. One of the most important of these was APC. Vogelstein and Kinzler showed that mutations of APC occurring in single colorectal epithelial cells are the initiating events in colorectal tumors, starting off the process and leading to the formation of benign tumors (adenomas). Furthermore, patients who inherit a mutation in APC develop a disease called familial adenomatous polyposis and develop hundreds or thousands of benign tumors throughout their colon and rectum. The team also discovered other genes that cause familial forms of colorectal cancers, including several that, when compromised, destroy the cell's ability to repair mistakes in its DNA. They have also identified genes, such as PIK3CA, that, when mutated, help convert benign tumors to malignant tumors.
Many of Vogelstein's current research projects are aimed at devising less invasive ways to diagnose cancer early and at discovering therapeutic approaches that will wipe out tumors by exploiting the new knowledge of cancer biology. His lab has developed sensitive blood tests that are now used in the clinic to identify patients with inherited mutations in genes known to be involved in colorectal cancer. Vogelstein and his colleagues are also exploring experimental treatments. For example, they've used an oxygen-hating, soil-dwelling bacterium to thwart tumor growth in animals with cancer. Because tumors grow so quickly, they tend to outrun their blood supply, leaving certain areas low in oxygen. Microbes that thrive in the absence of oxygen can penetrate tumors, proliferate rapidly, and kill the cancer cells.