Marking off new territory in the search for anticancer compounds
Epigenetic mechanisms add complexity and promise to cancer research efforts
Article first published online: 12 JUN 2012
Copyright © 2012 American Cancer Society
Volume 120, Issue 3, pages 143–144, 25 June 2012
How to Cite
Nelson, B. (2012), Marking off new territory in the search for anticancer compounds. Cancer Cytopathology, 120: 143–144. doi: 10.1002/cncy.21212
- Issue published online: 12 JUN 2012
- Article first published online: 12 JUN 2012
Cancer biology has long operated under the guiding principle that tumors arise from genetic mutations that are either inherited or acquired during a person's lifetime. As the rapidly growing field of epigenetics is making clear, however, the story is far more convoluted.
Scientists have learned that chemicals that latch on to the physical DNA helix and its closely associated histone proteins can increase the complexity of gene regulation by several orders of magnitude. These chemical tags, involving processes such as methylation and acetylation, can block or grant access to specific regions of the genome, essentially turning genes off and on. Unlike genes, however, these epigenetic switches may be far more easily manipulated, which is an exciting realization that could dramatically expand the pool of targets for anticancer drug design.
With 4 agents currently approved by the US Food and Drug Administration based on epigenetics and many more drugs in the pipeline, “we're clearly at a stage where we're moving toward maturity in the field,” says Jean-Pierre Issa, MD, director of the Fels Institute for Cancer Research and Molecular Biology at Temple University School of Medicine in Philadelphia, Pennsylvania.
Evolution of Epigenetics
Although the underlying concept of epigenetics has been around for decades, it gained momentum through studies suggesting that a mother's diet and nutrition during pregnancy could profoundly impact her child's well-being later in life. Other research focusing on identical twins concluded that their diverging behaviors and appearances could be driven in part by the accumulation of chemical alterations to their DNA. One particularly groundbreaking study found that British fathers-to-be who began smoking before reaching puberty had sons who were at a significantly higher risk of obesity and other health problems.1
Researchers now liken epigenetic marks to a cookbook edited by hand. Highlighting, annotating, and crossing out words may not erase the underlying text, but it can fundamentally change how each recipe is read. Running those pages through a scanner also transfers the majority of the notations to subsequent copies.
To date, epigenetics has left one of its biggest marks on the hunt for new cancer therapeutics. Dr. Issa and his colleagues have had some initial success in treating patients with leukemia using a DNA methylation inhibitor called SGI-110. Earlier in the drug pipeline, GlaxoSmithKline's GSK2816126 has shown promise against lymphoma by preventing an overactive enzyme from adding methyl groups to histone proteins and silencing tumor suppressor genes. A compound known as JQ1, tested by researchers at the Dana-Farber Cancer Institute in Boston, Massachusetts, in mice with myeloma, appears to suppress the influential MYConcogene by turning off one of its key regulators.
Earlier this year, a study led by scientists at Johns Hopkins University in Baltimore, Maryland, gave one of the first indications that the same general approach might work for patients with solid tumors.2 The exact mechanism of the epigenetic drug duo of azacitidine and entinostat has not been discovered to date, but it appears to work by reversing the abnormal silencing of important tumor suppressor genes. As a result, the regimen has helped several patients with advanced nonsmall cell lung cancer live significantly longer. The proof of principle “opens the floodgates for other academic centers as well as industry partners to see epigenetic events as viable targets for therapy in solid tumors,” says study coauthor John Wrangle, MD, MPH, a medical oncology fellow at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center.
Other experts have suggested that a more intriguing outcome of the study may be its support for the concept of resensitization, with its preliminary evidence that patients treated with the epigenetic drugs had better-thanexpected responses to subsequent chemotherapy. “The idea is that these drugs are resetting something in the tumors, making them more sensitive to other therapies,” Dr. Issa says, adding that other researchers are starting to observe the same phenomenon in similarly treated patients with breast and ovarian cancers. Dr. Wrangle's group is initiating a new trial to investigate the potential “priming” effect of the epigenetic drugs, and the area of inquiry is quickly shaping up as one of the hottest in the field.
Cancer cytopathologists are also beginning to take notice. Four years ago, for example, researchers reported that the combined methylation profiles of multiple tumor suppressor genes might be useful as a biomarker of precancerous high-grade squamous intraepithelial lesions in liquid-based Papanicolaou tests.3 Last year, scientists at the University of Heidelberg in Germany suggested that the lifecycle and pathology of cervical cancer-linked human papillomavirus may be regulated by epigenetics.4
The Future of Epigenetics
Scientists concede that mapping the entire epigenome and its interconnected regulatory pathways may be a gargantuan task, given that the body's 200-plus cell types each have their own unique profiles and that studies have yet to identify all of the chemical players. “Epigenetics is really difficult because there are infinite paths that you could follow, and you need to have some sort of cue as to which one to pick first,” says Amy Bernard, PhD, director of structured science at the Allen Institute for Brain Science in Seattle, Washington.
A growing list of ambitious projects may soon offer cancer researchers more guidance. The Allen Institute and Seattle's Swedish Neuroscience Institute, for example, are collaborating to create a 3-dimensional map of all gene activity within glioblastoma tumors, based on donated tissue from human patients. “I … think of our atlases as these Wikipedias of the brain,” says Dr. Bernard. The maps themselves do not provide epigenetic details, but rather are a good indication of where to start researching further by revealing the location and identity of genes that are turning on or off in intriguing ways. “How they got to be on or off in the first place, that's a question that is very dependent on the epigenetics,” Dr. Bernard says.
Even bigger efforts, such as the National Institutes of Health-funded Cancer Genome Atlas, have revealed multiple mutations in epigenetic regulators that had not previously been considered as potential targets for therapy. Just as researchers have based treatment strategies on genetic alterations, Dr. Wrangle points out, “understanding which tumors have a significant epigenetic driving force will be critical for choosing therapy in a rational and targeted way.”
BRYN NELSON IS A FREELANCE MEDICAL JOURNALIST.
CytoSource Reader Poll #6
Q: Within the next decade, cancer drug discovery based on epigenetics:
A. Will supply the bulk of new anticancer drugs.
B. Will be beneficial primarily for blood-borne tumors.
C. Will be useful mainly for sensitizing cancers to existing drugs.
D. Will not live up to expectations.
Take the poll online at www.cancercytojournal.com.
The results will be published in the October 25, 2012 issue.
FEBRUARY POLL RESULTS
Q: The use of comparative effectiveness research in cancer screening is:
100% Essential for sorting out the most beneficial tests and reducing cancer mortality.
0% Important but not essential.
0% Counterproductive in reducing cancer mortality.
0% Unimportant in reducing cancer mortality.
Content in this section does not reflect any official policy or medical opinion of the American Cancer Society or of the publisher unless otherwise noted. © American Cancer Society, 2012.