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Ep in Genetics

Ep in Genetics

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Published by: NEUHonors on Sep 20, 2012
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Epigenetics: A New Avenue for the Treatment of Lymphoma

Sean Burns Research Technician Dana-Farber Cancer Institute Northeastern University Introduction In 2009 in the United States alone, over 18,000 people perished from Non-Hodgkin lymphoma and over 70,000 new cases were diagnosed.[1] Additionally, this cancer is one of the fastest growing in worldwide incidence.[2] Researchers at Dana-Farber Cancer Institute have recognized this growing unmet clinical need and are eagerly working to design new therapies. In the past decade, new discoveries have led scientists to begin exploring the possibility of epigenetic treatments. While genetics seeks to understand how sequences of DNA affect organisms, epigenetics focuses on how the DNA is read by a cell. All cells in the body have the same DNA, but there are many different epigenetic bookmarks associated with DNA that establish the cell’s identity. Most importantly, cancer cells have been shown to acquire epigenetic tags that instruct them to divide uncontrollably. Recently, there has been a large effort to target these marks as a treatment for cancers. In the case of Non-Hodgkin lymphoma, one epigenetic mark in particular created more aggressive, destructive cancer cells.[3] By removing this tag, researchers hope to change the cell’s instructions, essentially causing the cancer cell to forget that it is cancer. With this approach, scientists can stop cancer cells from dividing, indicating that these treatments may be able to eradicate tumors in patients.[4] Biological Assays: Research tools for understanding and designing new drugs In drug development, many years of research are completed before a drug can be

given to patients. Several key experiments, known as assays, are conducted so that scientists can better understand how a drug will affect the body and whether the treatment will selectively target the patient’s cancer. This process sounds deceivingly simple, but modeling and understanding the intricacies of the human body is one of the greatest challenges in modern biology. In many experiments, tumor cells are extracted from patients and grown as a cell line representative of a certain type of cancer. These cell lines can then be tested with different potential drugs. As part of my research at Dana-Farber Cancer Institute, I have worked with many of these assays in Non-Hodgkin lymphoma cell lines to characterize molecules that have the potential to become epigenetic drugs. Western Blots The human body naturally generates antibodies which help the immune system recognize and attack foreign bodies, such as bacteria or allergens. By designing antibodies that recognize a specific epigenetic mark, scientists take advantage of these natural agents to understand how cells are affected by drug molecules. In the figure below, the presence of epigenetic marks found in lymphoma are detected by antibodies and observed as bands.

Fig 1. Western blots indicating the presence or absence of epigenetic tags. As seen in Figure 1, drugs 2-4 are very effective in decreasing the amount of mark 1 found in the cells. Cancer cells that depend on this mark to survive are likely to be killed by the drug, indicating that the drug may be an effective treatment for patients.

Immunohistochemistry Building on the principle of western blots, scientists developed methods for using antibodies to image complete cells in a process known as immunohistochemistry. Researchers can link fluorescent dyes to antibodies that recognize specific marks in the cells, and when imaged by a camera, the epigenetic marks can be visualized.

cells. The beads are then washed, leaving behind only the proteins that are interacting with the drug molecule. Using this approach, scientists can ensure that the molecule is truly affecting the target protein. In addition, other unknown mechanisms of the molecule are elucidated by unexpected interactions that pull down other proteins. Conclusion After validating the effect of drug molecules in the described assays using Non-Hodgkin lymphoma cell lines, scientists can move forward with studying the molecules in preclinical animal studies. The culmination of the experiments provides a fuller picture of the potential of the drug. Depending on the efficacy and safety of the tested molecules, the treatment may eventually advance into clinical trials. References [1] Howlader N., et al. SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations), National Cancer Institute. Bethesda, MD [2] Muller A., et al. Epidemiology of nonHodgkin’s lymphoma (NHL): trends, geographic distribution, and etiology. Annals of Hematology. 2005; 84: 1-12. [3] Sneeringer C., Coordinated activities of wild-type plus mutant EZH2 drive tumorassociated hypertrimethylation of lysine 27 on histone H3 in human B-cell lymphomas. PNAS. 2010: 107: 49. [4] Yoo C., Jones P., Epigenetic therapy of cancer: past, present and future. Nature Reviews. 2006: 5: 37-50. [5] Peters A., et al. Partitioning and Plasticity of Repressive Histone Methylation States in Mammalian Chromatin. Molecular Cell. 2003: 12: 1577-1589.

Fig 2. Immunofluoresence staining in embryonic stem cells [5] In Figure 2, the cells on the left are significantly brighter, indicating that these cells have much more of the mark that researchers are looking for. Scientists can also distinguish where in a cell a certain mark can be found. The cells on the right only contain the fluorescent dye in their nuclei, whereas the cells on the left have the stain throughout the whole cell. Using this approach, different drugs can be tested, and their effect on cancer cells can be compared visually. Chemical Proteomics While most drug development starts with a protein target and tries to design molecules that will interact with it, chemical proteomics takes a reverse approach. Chemical proteomics starts with a working drug and then identifies what proteins the drug is interacting with. This new technique in drug development is sometimes referred to as a “pulldown” or even more informally as “fishing” because the drug is used as bait to pull proteins out of cellular extract. The drug is immobilized on plastic beads and then mixed in with proteins extracted from

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