Culprit In Eye Cancer Identified
Very soon, there may be new hope for patients with a deadly cancer that strikes the eye. The cancer is uveal melanoma. Targeting the disease has proved elusive, and treatment has been unsatisfactory.
Now, researchers led by UCSF skin pathologist Dr. Boris Bastian have identified a culprit in the disease, and report their discovery in the Dec. 10 online edition of the journal Nature. Bastian already has begun collaborating with a biotech firm to investigate a new treatment strategy based on the finding.
Uveal melanoma is a type of cancer that arises in pigmented cells known as melanocytes. Melanocytes give rise to moles and, most infamously, to the most deadly skin cancers.
Not all melanomas arise from the outermost layers of living skin tissue, however. Uveal melanoma strikes melanocytes in the eye, specifically within the choroidal plexus — behind the iris or white of the eye, in the muscle tissue that controls pupil contraction, or within the surrounding, vessel-rich tissue.
Researchers, including Bastian, earlier identified genetic mutations that are responsible for melanomas arising on the skin. Clinical trials targeting those abnormalities are already underway. But those genetic mutations are not responsible for uveal melanoma. Tumor cells in uveal melanoma also appear different than the tumor cells in other melanomas.
Most strikingly, over time, uveal melanoma almost inevitably spreads through the bloodstream to the liver — a deadly turn of events. Treatment is ineffective. "Chemotherapy does not work. Radiation does not work," Bastian says.
The research reported in Nature was a team effort by Bastians lab and the lab of Stanford University researcher Dr. Gregory Barsh.
Bastian had heard Barsh give a talk at a scientific meeting, describing genetic mutations that gave rise to strangely pigmented mice. Bastian noted that the spread of pigmented cells in the mice described by Barsh, which arose in a deep skin layer, was similar to certain moles in humans called blue nevi. Blue nevi look blue because of the refraction of light through layers of skin that is caused by the pigmented cells situated in the deeper portions of the skin.
Bastian approached Barsh and postdoc Catherine van Raamsdonk with the idea of looking for similar mutations in human pigment cell tumors.
Sure enough, the researchers found a mutated form of a previously obscure gene called GNAQ — a form not found in normal skin or normal melanocytes — in the majority of the blue moles and almost half of uveal melanomas studied. All the mutations gave rise to the same abnormal form of the gene.
Bastian determined that the mutant gene gives rise to rapidly growing tumors in mice that were inoculated with mouse melanocytes carrying the mutant gene. The mutated form of GNAQ is a newly identified cancer growth-promoting gene, or oncogene.
Uveal melanomas strike about 1,500 people in the United States each year. Caucasians are disproportionately at risk. A form of blue nevus, called nevus of Ota, in which subtle pigmentation is found around the skin of the eye and on the clear membrane covering the white of the eye, is associated with increased risk for developing the cancer.
On Dec. 10, 2008, Alnylam Pharmaceuticals of Cambridge, Massachusetts, announced a collaboration with UCSF and Bastian to evaluate the potential of targeting the mutated form of GNAQ, using a strategy called RNA interference, or RNAi.
As the name implies, RNAi interferes with the production of proteins from specifically targeted genes. Alnylam has patented and licensed technologies to achieve systemic delivery of RNAi-based medicines, including technologies that might be used to develop an RNAi therapeutic to treat uveal melanoma.
While an RNAi approach can be used against many targets, it might prove to be especially good for targeting uveal melanoma cells that have spread in deadly fashion, according to Bastian. When it spreads, uveal melanoma spreads to the liver in 95 percent of cases.
"RNAi tends to be sucked up by the liver," Bastian says. "Here, we have a deadly cancer that metastasizes directly from the eye to the liver. Median survival after metastatis becomes apparent is seven months. As quickly as we can, we aim to develop a treatment that improves that prognosis."