Using epigenetic drugs against lymphoma

The human genome contains a little more than 20,000 protein-coding genes, providing the body with a lifetime of hereditary information for building and maintaining cells, according to the Human Genome Project.

Scientists and researchers have found that during the processes of a disease such as cancer or epilepsy, the regulation of the genome can become abnormal, possibly triggering the disease state or helping it progress.  The study of controlling the genome by means other than DNA sequence led to a new field called epigenetics – that led to epigenetic drugs.

Catharine Smith, associate professor in the Department of Pharmacology and Toxicology, and Arizona Cancer Center member, is working on ways to control the genome utilizing drugs that target specific areas in genes to fight off disease.

“The advantage of these drugs is that they really don’t have very harsh side effects,” Smith says. “Where a lot of drugs fail is that they are too toxic at the doses we would need to treat the disease.”

Smith, who is also a member of BIO5 Institute and the Southwest Environmental Health Sciences Center, has been investigating drugs referred to as histone deacetylase inhibitors that have been approved by the Food and Drug Administration for treating lymphoma. Lymphoma is a type of “blood cancer” that can arise from the T or B lymphocytes in the immune system. The disease drives the white blood cells to divide abnormally, eventually generating malignant cells which form tumors in the body.  Two histone deacetylase inhibitors have been approved specifically for a type of lymphoma that targets the body's T lymphocytes, which is very rare.  Smith's studies are aimed at determining how these drugs could be used effectively against the most common form of lymphoma, diffuse large B cell lymphoma.

According to Smith, histone deacetylase inhibitors are considered epigenetic drugs. Inside the cells of a human body genes are transcribed to RNA (ribonucleic acid) containing encoded genetic information. This information is then used to make individual proteins to regulate the function of proteins cells use various enzymes to chemically modify proteins after they have been made.  “For every chemical modification, there is an enzyme that puts it on and one that takes it off,” Smith says. “The deacetylase inhibitors inhibit the enzymes and remove acetyl groups from proteins.”  The reason these drugs are considered epigenetic is because they remove acetyl groups from histone proteins which regulate DNA access.  

 In the case of lymphoma, the goal was to cause the cells to either die off or stop rapidly dividing by targeting these chemical modifiers.

The human body has two meters of DNA in every cell. The DNA is held inside the nucleus, which is only 10 microns in diameter. That’s a difference of 10 to the 6th, according to Smith. The reason this can happen is because the DNA wraps itself around clusters of histones to achieve a level of compaction that allows it to fit into the nucleus of a cell. This mixture of histones and DNA is called chromatin.  The addition of acetyl groups to histones helps them to regulate DNA folding and unfolding. Genes in highly compacted regions of chromatin will not be expressed because the enzymes necessary for copying the DNA into RNA cannot access the DNA.  Acetylation of histones leads to unfolding of chromatin which opens up DNA to allow for transcription.  Inhibition of the enzymes which remove the acetylation with the drugs can thus change chromatin compaction and lead to changes in gene expression. Histone deacetylase inhibitors have been shown to cause cancer cells to either die off or stop rapidly dividing, which is why they are considered anti-cancer therapeutics.

Smith belongs to a group of scientists in the Arizona Cancer Center that has been working hands-on with these drugs to figure out how to maximize the efficiency of their impact on the B cell lymphomas. Smith’s lab group has focused on understanding why some lymphoma cells are resistant to HDAC inhibitors. This knowledge will be used to select other drugs that might be combined with HDAC inhibitors to strengthen their cell-killing effects. The investigative work involves some trial and error because drugs don’t always work as expected.

"I enjoy this a lot because it is a new field and you can really make a difference," says Smith. "I feel like I can make an impact on improving treatment for a particular lymphoma that's kind of nasty" because it’s common and aggressive.

Story and photos by Isaac Cox