Chemical inhibitor may provide lung cancer treatment

Glycosylation is an essential process for all cells, but researchers have long thought that there is no way to disrupt glycosylation in cancer cells without disrupting the same process in other cells and thereby causing serious harm, according to Joseph Contessa, a senior author of the study. The inhibitor identified in the study -- called NGI-1 -- affects tumor cells most severely, while leaving other cells relatively unharmed.

"This is important to cancer research because what we're looking for are therapies that don't have a lot of effect on normal cells but do have a lot of effect on tumor cells, and this falls into that category," said Contessa, the director of Yale's Central Nervous System Radiotherapy Program and an associate professor of therapeutic radiology and of pharmacology.

The researchers, who collectively were associated with Yale, the Broad Institute, the University of Massachusetts Medical School, the University of Kansas, the University of Georgia and the University of Texas Southwestern Medical Center, screened over 350,000 chemical compounds in an effort to find a substance that could partially disrupt glycosylation. Eventually, the researchers identified the inhibitor NGI-1 as having the desired effect. Cecilia Lopez-Sambrooks, the first author of the study, said that it was largely a team effort.

NGI-1 disrupts the growth of cancerous cells by blocking the glycosylation of oligosaccharyltransferase, an enzyme known as OST that transfers sugar molecules called oligosaccharides to receptor proteins, according to the study. OST plays an important role in the spread of cancer, as it is used to glycosylate receptor proteins on which tumor cells depend for growth.

According to Contessa, when the glycosylation of OST is blocked, however, the enzyme loses its ability to properly glycosylate the receptor proteins, which in turn hinders the growth of tumor cells. The study claims that NGI-1 only seems to limit the spread of cells dependent on the protein receptors EGFR and FGFR, meaning that it can specifically target the growth of cancer cells while having little effect on non-cancer cells.

Contessa likened the use of NGI-1 to that of a "dimmer switch." While most people have previously thought of glycosylation as something that can be switched on or off for all cells, NGI-1 only partially blocks glycosylation, which in turn has the most effect on tumor cells highly dependent on EGFR and FGFR, he said.

On Oct. 3, the study was published in the journal Nature Chemical Biology. Moving forward, Contessa said he hopes to bring the information from the study back to the clinic. He added that, ideally, this research can provide an alternative to other forms of treatment such as radiation therapy.

According to the study, the results "identify OST inhibition as a potential therapeutic approach to treating receptor-tyrosine-kinase-dependent tumors."

Contessa suggested that since NGI-1 is a relatively small molecule, it's likely that it could be ingested by the patient in the form of a pill.

"We have therapies, and they're good therapies, but they're not enough," Contessa said. "We need to take the next step."

According to the American Cancer Society, lung cancer is the leading cause of cancer death among American men and women. One in four cancer deaths in the United States result from lung cancer.