For half of patients with uveal melanoma, this rare cancer of the eye ultimately metastasizes to the liver. Once in the liver, the prognosis is bleak: patients typically live 2 to 9 months after diagnosis. Patients whose cancer has metastasized have few options for treatment. Recently, however, scientists conducting research on various treatments may have discovered the answer: a compound called FR900359 (FR), found in Christmas berry primrose plants of the Ardisia crenata species. With further testing, this compound could potentially become a treatment for uveal melanoma.
"I'm very optimistic," stated one of the study's authors, Jeffrey Benovic, PhD, Thomas Eakins Endowed Professor of Biochemistry and Molecular Biology at Thomas Jefferson University and Associate Director of the Sidney Kimmel Cancer Center. "If the results are confirmed in animal models and eventually humans, it could offer a new way to treat metastatic uveal melanoma patients down the road."
In this laboratory study published in Molecular Cancer Research, researchers analyzed the effects of FR on mutations of G proteins, Gaq and Ga11, which are observed in approximately 93% of all uveal melanomas. FR900359 inhibited cancerous Gaq and Gaq11 signaling in uveal melanoma cells expressing either mutant Gaq or Ga11, resulting in cell cycle arrest and ultimately in cell death. Once uveal melanoma cells were treated with FR, they appeared to transform back into melanocytes (normal skin cells). In addition, in higher doses, FR killed the cancerous cells.
"We didn't expect it would work because previous research suggested a related compound called YM-254890 did not inhibit the mutated forms of the proteins found in uveal melanoma," explained the study's lead author, Dominic Lapadula, a graduate student in Dr. Benovic's lab, "but lo and behold, FR very effectively blocked the growth of the uveal melanoma cells."
Dr. Benovic added, "FR appears to be able to help reset the cells back to their normal state. Ideally, that's what you want."
Next, the researchers will be working with Takami Sato, MD, PhD, Director of the Metastatic Uveal Melanoma Program at Jefferson, in order to replicate these findings in a mouse model of uveal melanoma.
"I'm hopeful FR and related compounds will reset the cancer cells in the mouse model as it did in the cells we grew in the lab, getting it one step closer to test in humans," Dr. Benovic remarked.
For More Information
Lapadula D, Farias E, Randolph CE, et al (2018). Effects of Oncogenic Gaq and Ga11 Inhibition by FR900359 in Uveal Melanoma. Mol Cancer Res. [Epub ahead of print] DOI:10.1158/1541-7786.MCR-18-0574
Image courtesy of Batholith