Rutgers Professor Suzie Chen has found that riluzole, a U.S. Food and Drug Administration (FDA) approved drug used to treat Lou Gehrig's disease (ALS), slows the growth of melanoma, the most aggressive form of malignant skin cancer.
A Phase 0 (zero) clinical trial of riluzole (brand name Rilutek), conducted by James Goydos, a surgical oncologist with The Cancer Institute of New Jersey (CINJ), is in process with a small group of late-stage (stage 3 or 4) melanoma patients. Phase 0 is a recent designation by the FDA for exploratory, first-in-human trials. Goydos reported preliminary but encouraging findings from the trial during a plenary session today at the annual meeting of the American Association for Cancer Research in San Diego.
In about 70 percent of melanoma cases, the disease appears in places that are exposed to the sun. It can then spread to other parts of the body and may become lethal. This type of cancer is not generally responsive to chemotherapy. According to a report from the National Cancer Institute, the incidence rate of melanoma has more than doubled in the past 20 years in the United States.
Chen had reported in 2003 the discovery of a gene – Grm1 – responsible for melanoma in laboratory mice. Its normal functions are in the brain, where it is associated with learning and memory; but when this gene is expressed or turned on in certain skin cells, it leads to the development of melanoma.
A common feature to both ALS and melanoma cells is excess glutamate, a cellular growth factor or food for cells. An excess of this protein can overstimulate neurons to the point where they burn out – a possible explanation of what happens in ALS.
In a melanoma cell, the glutamate enters a pernicious loop where it binds to the malfunctioning cell surface protein. The protein operates as a receptor, stimulating the cell to produce more glutamate that, in turn, binds to the receptor, stimulating more production. This cellular “overfeeding” results in the growth and expansion of the melanoma.
“We fixed on riluzole because it is a known inhibitor of glutamate release, the suspected culprit in ALS and possibly melanoma,” said Chen, a professor of chemical biology at the Susan Lehman Cullen Laboratory of Cancer Research in the Ernest Mario School of Pharmacy of Rutgers, The State University of New Jersey, and a CINJ member. “While most of our studies five years ago were with animals, it is humans that we are really interested in.”
In new laboratory experiments using cultures of human melanoma cell lines, riluzole appeared to shut off the glutamate, thus slowing the growth rate of the melanoma cells. Moving forward with animal studies, riluzole demonstrated the same suppression of tumor cell growth and progression seen in cultured cells.
Building on this foundation, Chen joined Goydos to pursue human clinical trials. Goydos is a surgical oncologist and director of the Melanoma and Soft Tissue Oncology Unit at the Cancer Institute of New Jersey, part of the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School (UMDNJ-RWJMS). Goydos is also an Associate Professor of surgery at UMDNJ-RWJMS.
A grant from the National Cancer Institute enabled Goydos to begin an initial or Phase 0 trial. The use of late-stage patients is a requirement. It is a purely experimental exercise designed to make sure the drug that appeared to work in pre-clinical trials is actually performing as expected in humans – “to see if you are hitting your targets,” as Goydos phrased it.