This zebrafish has melanoma, with dark-colored tumors visible around and above the eyes. (Courtesy of the Yariv Houvras lab at Weill-Cornell Medical College.)
“I trained as a pure chemist,” says epigenetics investigator Minkui Luo, “and I knew very little about cancer before I came here.” However, since he joined the Memorial Sloan Kettering faculty in 2008, Dr. Luo’s research has taken him deep into largely unexplored territories of cancer science — and toward the making of a new drug he hopes will help patients one day.
Dr. Luo’s laboratory specializes in epigenetics, the study of genetic changes that are not part of the DNA code. Their research is focused on a group of epigenetic enzymes called protein methyltransferases (PMTs), which control gene expression by modifying histones — proteins that form the structures around which DNA is wrapped — and other molecules. Together with physician-scientist Yariv Houvras at Weill-Cornell Medical College, Dr. Luo has found that a PMT called SET8 could be a promising target in the development of new cancer drugs.
A Striped Fish
By screening a library of small drug compounds, Dr. Luo’s team identified and optimized several therapeutically potent substances that could inhibit the activity of SET8. Working in a zebrafish model of melanoma developed in Dr. Houvras’s lab, they found that these compounds had powerful anticancer effects.
How the Richard White Lab Studies Zebrafish to Understand Cancer
Zebrafish naturally succumb to some of the same diseases as humans, including melanoma. They make elegant cancer research tools for a number of reasons, one being that their melanoma tumors are as dark as ink. Researchers can see the cancer develop with the naked eye, or watch tumors shrink in response to a drug.
“We got very excited when we found the SET8 inhibitor could block one of the key pathways known to drive melanoma, called the MITF pathway,” Dr. Luo says. “Meanwhile, other scientists reported SET8 might also be involved in metastatic breast cancer, so we knew we were onto something.”
Refining the Drug’s Chemistry
PMTs regulate genes by placing chemical labels called methyl groups on certain sites of histones or other molecules. Because these marks are so tiny (a methyl group is a cluster of one carbon and three hydrogen atoms), the enzymatic activity used to be very difficult to study, Dr. Luo says. But his lab has developed a special technology — essentially a way to amplify molecular anatomy — that enables them to monitor the biochemical reactions. Using this and other chemistry methods, they are working to optimize the pharmacological properties of the SET8 inhibitors with the goal to generate a more optimal drug that could be tested in patients.
The next step is to test the drug in mouse models of melanoma and metastatic breast cancer,” Dr. Luo says. “We want to see in what kinds of tumors it might have the best chance to work, whether it causes side effects, and at what dose and schedule it’s effective.” In addition, the researchers will continue to explore the biology of SET8 and whether it might be implicated in additional cancers.
