Researchers at the University of Florida Health Cancer Center, the Sylvester Comprehensive Cancer Center and Moffitt Cancer Center received a five-year, $3.95 million NIH grant to study how uveal melanoma spreads to the liver. This work was previously supported by a Florida Academic Cancer Center Alliance (FACCA) pilot and two Florida Department of Health Biomedical Research Program Bankhead-Coley grants.
Uveal melanoma affects the melanocytes (pigment cells) in the eye and is the most common adult eye cancer. Like most tumors, UM becomes increasingly deadly as it spreads to other organs, and for some reason, it especially focuses on the liver.
Two mutated proteins, Gaq and BAP1, play a major role in uveal melanoma progression and metastasis to the liver. How these mechanisms drive liver metastasis has never been comprehensively studied, according to J. William Harbour, M.D., professor and associate director for basic science at Sylvester, who leads the Sylvester arm of the study.
The scientific team, which includes Jonathan Licht, M.D., director of the University of Florida Health Cancer Center and Keiran Smalley, Ph.D., professor and Director of the Melanoma and Skin Cancers Center of Excellence at Moffitt Cancer Center, wants to understand how Gaq and BAP1 mutations pave the way for liver metastasis.
“Uveal melanoma is a devastating disease with few therapeutic options,” said Licht. “Our group will determine the mechanisms by which this disease metastasizes and will identify which of these may represent new targets for therapy.”
Typically, people get a Gaq mutation first, but most of the time, the body gets rid of those proliferating cells and people end up with a nevus or a mole. Sometimes, however, these cancers break through the body’s security measures — and one of those ways is through BAP1 mutations. The researchers want to understand why these two mutations go together in uveal melanoma, because they don’t often pair up n in other cancers.
The researchers believe the body may be preventing significant tumors by forcing Gaq-mutated cells into senescence – essentially, putting them to sleep. BAP1 mutations may reverse that program, allowing Gaq mutants to wake up, proliferate and invade other tissues. However, no one has fully investigated the specifics of this process.
“Uveal melanoma is a devastating disease with few therapeutic options. Our group will determine the mechanisms by which this disease metastasizes and will identify which of these may represent new targets for therapy.”Jonathan Licht, M.D., Director of the UF Health Cancer Center
Another important issue is why UM metastasizes so often to the liver. BAP1 may be implicated here as well. BAP1 mutations may influence a type of liver tissue called stellate cells, generating a protective niche for UM cells to nest, avoid immune cell surveillance and propagate into the liver.
“There may be common signaling pathways in the eye and the liver,” Harbour said. “These uveal melanoma cells could find a parallel environment in liver tissue that allows them to survive.”
The final step will be identifying molecules that can arrest liver metastasis. The team is looking at two epigenetic proteins that may be sensitive to BAP1 degradation (HDAC1 and HDAC4), adversely influencing gene expression in stellate cells. HDAC inhibitors may be a promising option to stop UM liver metastasis. The hope is to reverse the effects of BAP1loss in the liver, disrupt this stellate cell niche and improve patient survival.
“It’s been a great pleasure working with such accomplished colleagues as Drs. Harbour and Smalley and to enter the world of melanoma research,” Licht said.