In the latest chapter of a 15-year scientific story spanning the globe from the South Pacific to New Haven, a team of scientists in Yale’s Department of Chemistry has achieved the first synthesis of an elusive chemical compound, opening the door to the development of a new class of molecules to target and destroy cancer stem cells. Many researchers believe that these cells are a root cause of some of cancer’s deadliest characteristics, including resistance to chemotherapy, tumor relapse, and metastasis.
The story begins in 1996, when a team of scientists from Wyeth-Ayerst Research (now part of Pfizer) and the University of Utah were analyzing marine organisms they had collected in Fiji in the hopes of finding useful chemicals for drug development. From a bright orange sea squirt retrieved from the seabed, the group isolated a chemical that killed cancer cells and microbial pathogens such as staph bacteria with remarkable potency. The structure of the compound suggested that it might have a bacterial origin itself, and after five years of subsequent analysis the team discovered a previously unknown species of symbiotic bacterium living on the sea squirt that produced yet another chemical with impressive anticancer and antibacterial properties, which they called lomaiviticin.
But the bacterium that produces lomaiviticin is extremely rare, and it cannot be easily coaxed into creating the molecule in the laboratory. For the past decade, chemists worldwide have been striving without success to synthesize lomaiviticin to obtain sufficient quantities for exploring its anticancer properties more deeply. Now, as reported online January 31 in the Journal of the American Chemical Society, a team at Yale, led by Seth Herzon, Ph.D., has managed to synthesize a form of the compound known as lomaiviticin aglycon for the first time.
“About three quarters of anticancer agents are derived from natural products, so there’s been lots of work in this area,” says Herzon, assistant professor of chemistry. “But this compound is structurally very different from other natural products, which made it extremely difficult to synthesize in the lab.”
Herzon’s team, which managed to synthesize the molecule in just 11 steps starting from basic chemical building blocks, has been working on the problem since 2008 and spent more than a year on just one step of the process involving the creation of a carbon–carbon bond. It was an achievement that many researchers deemed impossible, trying to work around it using other techniques, but the Herzon team’s persistence paid off.
“A lot of blood, sweat, and tears went into creating that bond,” Herzon says. “After that, the rest of the process was relatively easy.”
In 2010, Herzon was named a Searle Scholar, an award granted each year to 15 “exceptional young faculty in the biomedical sciences and chemistry,” according to the program’s website.
In addition to lomaiviticin aglycon, Herzon’s team has also created smaller, similar molecules that have proven extremely effective in killing ovarian stem cells, says Gil Mor, M.D., Ph.D., a researcher at the School of Medicine and Yale Cancer Center who is collaborating with Herzon to test the new class of molecules as cancer therapies.
But Mor and Herzon are particularly excited about lomaiviticin aglycon’s potential to kill ovarian cancer stem cells because the disease is notoriously resistant to Taxol and carboplatin, two of the most common chemotherapy drugs.
“Ovarian cancer has a high rate of recurrence, and after using chemotherapy to fight the tumor the first time, you’re left with resistant tumor cells that tend to keep coming back,” Mor explains. “If you can kill the stem cells before they have the chance to form a tumor, the patient will have a much better chance of survival—and there aren’t many potential therapies out there that target cancer stem cells right now.” Cancer stem cells are thought to be precursors to tumors in a number of other cancers as well, including in the brain, lung, and prostate, and in leukemia.
Herzon, Mor, and colleagues will continue to analyze lomaiviticin aglycon to better understand its actions on cancer stem cells at the molecular level, and they hope to begin testing the compounds in animals shortly.
“This is a great example of the synergy between basic chemistry and the applied sciences,” Herzon says. “Our original goal of synthesizing this natural product has led us into entirely new directions that could have broad impacts in human medicine.”