Drug reactivates silenced genes

Researchers at Hopkins have discovered a set of genes that are turned off by cancer cells in their attempt to hide from the immune system. These genes were discovered by treating breast, colorectal and ovarian cancer cell lines with the FDA-approved drug 5-azacitidine. This drug, which reactivates silenced genes, exposed 16 different immune system related pathways that have decreased expression in cancer cells. Such decreased expression allows cancer cells to more easily invade tissues.

One mechanism by which molecular pathways can be silenced or activated is a change in epigenetic characteristics. Epigenetics refers to the study of changes in gene expression due to factors other than DNA sequence, such as environmental carcinogens, extreme fear or famine. Such sequence-independent changes were first recognized in the 19th century by Marcus Pembrey. Pembrey, interested in the effects of a Swedish famine, found that men who had been exposed to the famine as children had a lower probability of dying from cardiovascular disease than those not exposed to famine conditions as children.

Pembrey also found that differences in mortality extended beyond one generation; the men who lived with access to more food had a higher probability of having a grandchild who would die from diabetes. This link suggested that such environmental effects could be inherited over generations and thus was somehow encoded in the genome.

One of the main ways that epigenetics act is through the silencing of DNA. On a molecular level, this can occur through methylation of cysteine base pairs by enzymes called DNA methyltransferases. J.D. McGhee and G.D. Ginder were the first to first observe this process. In 1980, McGhee and Ginder analyzed the DNA sequences of the beta-globin genes in both the cells that expressed beta-globin and those that did not. They discovered that the cytosine base pairs in the DNA of cells that did not express beta-globulin was methylated.

5-azacitidine, the drug used in the Hopkins experiment, is a chemical analogue to cytosine and can integrate into DNA and RNA. When used in vitro, this drug severely inhibits methyltransferase activity.

Additionally, 5-azacitidine, marketed as Vidaza in the medical world, can treat myelodysplastic syndromes. In myelodysplastic syndromes, the bone marrow produces abnormal blood cells. 5-azacitidine preferentially integrates into the genome of abnormal blood cells, inhibiting their growth and duplication and ultimately leading to their death.

The Johns Hopkins University research team hopes to use 5-azacitidine in a two-step cancer therapy treatment plan. The initial dosage of 5-azacitidine would reverse the methylation of immune system genes. Once reactivated, the immune system could attack the unveiled cancer cells. Initial testing proved the potential advantages of this technique: out of the 6 patients tested, 4 had their cancer suppressed.

Sorry cancer cells, you’ve got nothing on Harry Potter.