Grant: Operating Grant

Human DNA is coated with chemical marks called methyl groups. The methyl groups (DNA methylation) program how genes function. This program is critical for normal life. In cancer, the distribution of the methyl groups on the DNA is altered. Drugs that modify the markings of DNA, called epigenetic drugs, are considered a novel approach to cancer therapy as well as to other diseases. However to be able to take advantage of these drugs we need to understand their mechanism of action. A drug blocking DNA methylation (Vidaza) is now approved for treating certain blood cancers. However, we discovered in the previous term of the grant that Vidaza does not only cause loss of methylation from tumor blocking genes, but it also removes the methyl marks from genes that cause metastasis, raising the concern that this anticancer drug would induce metastasis, the most morbid aspect of cancer. Our challenge is to discover ways to utilize this class of drugs to block cancer while avoiding metastasis. The first step is to understand the mechanisms of action of these drugs. Since multiple proteins called DNMTs 1 to 3 are involved in DNA methylation and Vidaza blocks them all, we first propose to test the impact of depleting just one of these proteins on the distribution of methyl groups in cancer and normal cells. We believe that by blocking a specific form of DNMT1 we will reduce the risk of metastasis. Second, we will determine whether inhibitors of DNMT will work in only in cells that are dividing and will thus be limited to fast growing tumors or also in nondividing cells and will therefore be useful in treating slow growing cancers, brain diseases and other diseases in organs where cell division does not occur. Third, we discovered that DNMT1 inhibitors could block cell growth without affecting the methyl coating, thus avoiding the risk of metastasis. We will define how DNMT1 is involved to determine whether this activity should be targeted in our drug design.