Scientists uncover new pharmaceutical strategy for treating melanoma

Roswell Park Cancer InstituteMay 6 2015

Scientists looking to better understand the mechanisms behind the origin and spread of melanoma tumors have uncovered a possible role for a decades-old antibacterial agent in treating these aggressive and increasingly common cancers. In findings reported in the journal Cell Death and Differentiation, the researchers demonstrate that a particular enzyme, guanosine monophosphate synthase (GMPS), drives melanoma growth, and propose a new pharmaceutical strategy for targeting that protein.

Following up on their earlier work that revealed the prominent role played by deregulation of guanylate metabolism in melanoma progression, researchers led by Mikhail Nikiforov, PhD, of Roswell Park Cancer Institute (RPCI), investigated the role of GMPS, a key enzyme in guanylate metabolism, in melanoma development and metastasis. Guanylates, as the precursors to one of the four bases that make up RNA, play a critical role in cells. The authors evaluated the effects of GMPS depletion and explored the possibility of targeting GMPS by angustmycin A, also known as decoyinine. While this compound was discovered in the early 1950s as a potential antibiotic, it has never been experimentally investigated as an antitumor agent nor investigated at all in clinical settings.

Dr. Nikiforov and colleagues demonstrate in this latest study that GMPS levels are increased in human metastatic melanoma specimens and that pharmaceutical inhibition of GMPS by angustmycin A has the potential to be effective as a targeted anti-melanoma therapy for tumors carrying either of the two most common mutations: BRAFV600E and NRASQ61R.

"These are early, preclinical findings, but they open up the exciting prospect of possibly treating melanoma with an inexpensive and well-tolerated agent," says Dr. Nikiforov, a Professor of Oncology in the Department of Cell Stress Biology at Roswell Park. "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." Dr. Nikiforov and team have begun further laboratory studies to investigate the antimelanoma efficacy of angustmycin A both as a standalone therapy and in combination with conventional therapy.

The paper, entitled "Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity," is available at nature.com/cdd/journal.

This research has been made possible in part by a generous donation from the Jennifer Linscott Tietgen Family Foundation, which is dedicated to supporting melanoma cancer research in memory of their daughter, Jennifer.

"When we lost Jennifer at a young age to melanoma, it was earth-shattering for our family," the Tietgens say. "We knew we needed to do something to make a difference, and the best way we could think of was funding melanoma research projects. The Roswell Park melanoma team has an advanced understanding of this devastating cancer and is working tirelessly to improve diagnostic testing and treatment."