Chemotherapeutic inhibition of polysialic acid biosynthesis
Initial Award Abstract
In 1912 lung cancer was a rare disease. That began to change in 1913 when R. J. Reynolds introduced the first modern cigarette - filterless Camels. Lucky Strikes, Chesterfields, and Philip Morris were quick to follow with brand name cigarettes of their own. As a direct consequence of increased tobacco smoking, by 1950 lung cancer was the leading cause of cancer related deaths among men in the United States. As it became socially acceptable for women to smoke, lung cancer deaths increased in this group as well. In recent years, more than 150,000 people in the U.S. have died of lung cancer annually, and smoking tobacco caused more than 90% of those cases. Lung cancer is often incurable, and of all types of cancer, lung cancer is among the most fatal diseases.
Lung cancer goes through several stages of development including a stage where cells grow uncontrollably, tumors form, and the cancer begins to spread to other parts of the body. All too often, once the cancer begins to spread, death is not far behind. For certain types of lung cancer, there is a very short period of time between rapid cell growth and spreading of the cancer to other organs or tissues. Although chemotherapy is most often used to treat lung cancer, it rarely leads to a cure when the cancer has already spread. Therefore, it would be very beneficial to have drugs that could stop the spread of the cancer at an early stage. The proposed research will develop methods for making a new class of compounds that are designed to slow and perhaps stop the spread of tobacco related lung cancer.
The spread of cancer is a complex process but we are aware of certain factors that may be involved. For example, in some lung cancers there are long chains of carbohydrates that appear on the cancer cell surface. These carbohydrate chains are composed of a single sugar molecule known as sialic acid and each sialic acid unit is connected to the neighboring sialic acid unit through a specific linkage. The cancer cell uses an enzyme to produce the long chain carbohydrates. These long chain carbohydrates (or polysialic acids) serve to increase the mobility of the cells, which increases their capacity to invade and spread to other tissues. Our hypothesis is that if the production of long chain carbohydrates can be prevented, the spread of lung cancer will be slowed or stopped. The polysialic acids are formed in an enzymatic process that uses a single carbohydrate known as CMP-Sialic Acid.
During the past year, molecules that structurally resemble CMP-Sialic Acid have been synthetically prepared, and it has been shown that they inhibit the incorporation of sialic acid into growing carbohydrate chains. These studies were made possible by the development of a new, facile in vitro assay that is amenable to rapid screening of large collections of compounds. In the next year of this grant we will expand the synthesis component to include second and third generation candidates and demonstrate that these compounds enter cancer cells and prevent the production of polysialic acid. The next step will be to show that the prevention of polysialic acid formation also leads to diminished capacity of the cells to spread. |