Genetic engineering could salvage once-promising anti-cancer agents

A group of anti-cancer agents that once produced dismal results in clinical trials could once again be a promising tool in fighting the deadly disease, thanks to research by a team of chemists at the University of Washington and in Germany.

The agents, called maytansinoids, were first discovered in the 1970s when scientists looked for tumor inhibitors in a rare Ethiopian plant. The same group of maytansinoids was later isolated from a new bacteria species. The compounds held great promise because of their exceptional potency, and early tests indicated they were effective against some tumors and leukemia lines.

But the compounds were difficult to come by in quantities large enough to manufacture drugs and, when potential treatments were developed, they proved too strong when tested in clinical trials.

“These compounds were too potent. They were toxic to patients,” said Tin-Wein Yu, a UW research assistant professor of chemistry. “We thought if we could modify the chemical structure to make the agents more appropriate for cancer patients, that would be beneficial. And we could use the same strategy to ease the side effects.”

UW researchers headed by Heinz Floss, an emeritus chemistry professor, teamed with researchers from Rheinische Wilhems-Universität in Bonn, Germany, to develop ways of modifying genes that create maytansinoids and then produce cancer treatments that are more effective against tumors and better tolerated by patients.

Their efforts essentially relied on using the modified genes to produce the anti-cancer agent. The first step was to locate the genes that control maytansinoid formation and clone them. They first gained access to genes that control maytansinoid production, then altered the maytansinoid structure at the genetic level.

“If you can manipulate the production genes, it makes the process much easier,” said Yu, who is the lead author of a paper describing the work in the June 11 issue of the Proceedings of the National Academies of Science.

To clone the genes, the researchers snipped the genome of the bacteria (Actinosynnema pretiosum) into small bits to create a genomic library. They used a gene that already had been cloned from another microorganism (Amycolatopsis mediterranei) as a reference to screen the library and find the genes needed for maytansinoid construction. Having access to the genes that control the formation of maytansinoids allows scientists to manipulate the structure of the anti-cancer agent at the DNA level.

The work, for which the UW has applied for a patent, allows for a detailed analysis of maytansinoid formation at both the genetic and biochemical levels. It also sets the stage to modify maytansinoids through genetic engineering, so they are less toxic to humans, are more effective against cancer and bond easily with delivery agents.

Several companies are in discussions about the possibility of using the research to combine maytansinoids with antibodies that target tumors. The antibodies would search out specific cancer antigens attach only to cancer cells, Yu said. The maytansinoids then can enter the cancer cells and destroy them without damaging surrounding healthy tissue.

“It is a warhead strategy,” he said.

The work has provided researchers with a number of options other than simply deciphering the biosynthesis of pre-existing compounds, Yu said. Manipulating the structure, he said, ultimately could lead to development of more effective cancer drugs.

The research was funded by grants from the National Institutes of Health, Deutsche Forschungsgemeinschaft (Germany’s central public funding organization for academic research), the Fonds der Chemischen Industrie in Germany and the North Atlantic Treaty Organization.

For more information, contact Yu at (206) 543-3791 or yu@u.washington.edu