Old is new again

BUFFALO, N.Y.—A compound that was discovered in the early 1950s could be the key to more effective melanoma treatment, report scientists at the Roswell Park Cancer Institute (RPCI). A new study suggests that angustmycin A, which has previously been treated as an antibiotic, has the potential to be effective at targeting melanoma tumors carrying either of the two most common types of cancer mutations: BRAF and NRAS.

“These are early, preclinical findings, but they open up the exciting prospect of possibly treating melanoma with an inexpensive and well-tolerated agent,” according to Dr. Mikhail Nikiforov, a professor of oncology in the Department of Cell Stress Biology at RPCI.

Nikiforov tells DDNews that his team’s discovery that angustmycin A has the potential to treat melanoma followed from their finding that the enzyme guanosine monophosphate synthase (GMPS) plays a central role in driving melanoma growth. After revealing the role of GMPS, the researchers began searching for a compound that could therapeutically target the enzyme.

“We wondered whether there was any already-known GMPS inhibitor available and, if so, whether any test had been carried out already in a tumor setting,” Nikiforov tells DDNews. “We found that angustmycin A is one of the most specific GMPS inhibitors.”

The findings come from a study recently published in the journal Cell Death & Differentiation and are the culmination of a longstanding research effort in Nikiforov’s lab focused on the deregulation of guanylate metabolism in melanoma. Guanylates play an important role in cells as the precursors to one of the four bases that make up RNA.

In previous studies, the researchers demonstrated for the first time that that one of the enzymes involved in guanylate metabolism was a suppressor of melanoma invasion. This enzyme, called guanosine monophosphate reductase (GMPR), works toward reducing the amounts of guanylates in the cell. Inhibition of GMPR, which results in increased guanylate pools, was shown to lead to increase invasion of melanoma cells while its over-expression abrogated their invasive capability. They also found that GMPR expression strongly decreased as tumors progressed from primary in situ to invasive, and even more as they developed into metastatic melanomas.

In their most recent study, the researchers turned to the role of GMPS, an enzyme that Nikiforov describes as “a functional antagonist of GMPR in melanoma maintenance.” His lab found that GMPS plays a major role in driving the invasive potential of melanoma cells through its ability to positively regulate guanylate pools. “Oppositely to GMPR, GMPS expression is maintained and/or induced during melanoma progression, rendering it a suitable target for therapeutic intervention,” says Nikiforov.

The researchers ultimately found that angustmycin A could provide an effective means of therapeutically inhibiting GMPS. “Angustmycin A is a compound that was isolated from fungi in the mid-50s to be used as a potential antibiotic, but it has never been tested in clinic,” Nikiforov tells DDNews. “To the best of our knowledge, angustmycin A has never been tested before for antitumor activity.”

Currently there is no specific therapy against melanoma carrying NRAS mutations, while melanomas with BRAF mutations are treated with specific BRAF inhibitors. However, about one-third of patients with BRAF mutations do not respond to these drugs, and most of the responders relapse within roughly six months. The RPCI study found angustmycin A to be effective in vitro and in vivo against melanoma cells, regardless of whether they involved BRAF or NRAS mutations.

Nikiforov and his team are continuing to pursue several lines of research that will build on their recent findings. One focus of these studies will be the antimelanoma efficacy of angustmycin A both as a standalone therapy and in combination with conventional therapy.

“We are conducting a more in-depth investigation of the mechanisms of action of angustmycin A as well as exploring its potential as a standalone therapy or in combination with currently used drugs to obtain, hopefully, a synergistic effect,” Nikiforov says. “And because we have previously shown that guanylate pools can influence the invasion of cell lines derived from other types of cancer as well, we are also excited about the possibility of uncovering widespread mechanisms and targets that can be common to other kinds of tumors.”