MERIT Award Recipient: Bert Vogelstein, M.D.
Molecular Genetic Analysis of Colorectal Cancers
Tumors of the colon and rectum are a major health problem: in 2002 alone, a million new cancer cases occurred in the world, resulting in ~590,000 deaths. Half of the population of the United States will develop at least one benign colorectal tumor, and in one-tenth of these, the tumors will eventually become malignant. Research in Dr. Vogelstein's laboratory is aimed at understanding the molecular basis of colorectal tumors in the hope that this knowledge can be used to improve diagnosis and therapy.
During the past five years, Dr. Vogelstein and his colleagues discovered several novel genetic alterations in colorectal tumors that are critical for its development. The most important of these affected PIK3CA, a gene mutated in more than 30% of the tumors. Subsequent research showed that this gene was altered in a variety of other common cancers, including those of the breast, stomach, liver, ovary, and lung. The PIK3CA gene is therefore one of the most highly mutated genes ever identified in human cancers.
Current efforts are devoted to understanding the role of PIK3CA in human cancer and exploring ways to use this information to help patients. PIK3CA encodes an enzyme that can modify lipids. Such modified lipids induce cells to grow more robustly and to resist signals that would normally cause them to die. State-of-the-art molecular genetics techniques will be used to disrupt the mutant PIK3CA gene in colorectal tumor cells and observe the biochemical and physiologic properties of such cells. This will provide clues that explain exactly how the modified lipids produced by mutant PIK3CA genes affect tumor growth. Using X-ray crystallography, the molecular structure of various forms of PIK3CA enzyme will be determined. Such structures will provide insights into the mechanisms through which PIK3CA mutations affect enzymatic function. Finally, high throughput methods for drug discovery along with sophisticated synthetic chemistry will be employed to identify agents that can inhibit the PIK3CA enzyme. Such agents will be tested in experimental tumors in mice to predict whether they will be useful for the therapy of the many patients whose tumors contain mutant PIK3CA genes.