Melanoma of the Eye: Better Diagnostics and Future Treatments

Laitr Keiows / Wikimedia Commons Laitr Keiows / Wikimedia Commons

Ocular melanomas, or melanomas found in the eye, are fairly infrequent, but they are the most common type of eye tumor. In the U.S., there are about 2,000 cases diagnosed each year. They occur within one of the three parts of the eye: the iris, the choroid, or the ciliary body. Collectively, these are known as the ‘uvea,’ hence an alternative name for this cancer: uveal melanoma.

Ocular melanomas are often treated with surgical removal of the tumor and sometimes the entire eye. They can also be treated with a form of radiation therapy known as brachytherapy, in which a small disk with highly radioactive material is placed on the surface of the eye for a few days to kill tumor cells.

Additional treatment options have been elusive; cutaneous (skin) melanomas, which are far more common, can often be treated with targeted therapy drugs. Almost half of cutaneous melanoma patients’ tumors have mutations in a gene called BRAF, and there are three targeted therapy drugs approved for treating BRAF-mutant melanoma. Ocular melanomas almost never have mutations in BRAF, but over 80% have cancer-promoting mutations in one of two genes: GNAQ and GNA11. Unfortunately, unlike for BRAF, there are no drugs that directly target GNAQ or GNA11.

However, just a few days ago, two teams of scientists from the University of California, San Diego  and the National Institutes of Health reported that they have identified a cellular protein, named YAP, that is abnormally active in ocular melanomas with mutant GNA11 or GNAQ. High activity of YAP is responsible for the development and progression of ocular melanomas. This is an important finding for understanding the pathogenesis of ocular melanoma, but it is all the more exciting because a drug that targets YAP already exists. This drug, verteroporfin (brand name Visudyne), is prescribed to eliminate the growth of abnormal blood vessels involved in macular degeneration. Turns out, verteroporfin is also an inhibitor of YAP. This opens a direct route to clinical trials to test verteroporfin in volunteer ocular melanoma patients.

Oncologists studying ocular melanoma have also been looking into better ways of predicting a patient’s risk of metastasis, also based on abnormal genetic characteristics of the tumor. Similarly to other types of melanoma, ocular tumors tend to metastasize after the primary tumor is eradicated. Most metastases occur in the liver; other organs can be involved, albeit much less frequently. Metastases can occur late—10 or even 15 years after treatment—and they show up in about half of all patients.

Obviously, it is imperative to identify patients at risk of developing metastases and to treat them with some form of therapy soon after surgery or radiation. And, of course, identifying patients at low risk of metastasis is important as well, so as not to subject them to unnecessary and harsh treatments. The old option of scanning the livers of patients every 6 months after surgery does not really work. By the time scans show the presence of metastases, not much can be done to save lives.

Much work has been done on defining prognostic factors in ocular melanoma, for example, finding links between certain characteristics of a tumor and the likelihood that it will shed cells into the bloodstream to form liver metastases. One such indicator was found: healthy cells normally have two copies of every chromosome, but ocular melanoma tumors that lack one of their two copies of chromosome 3 are more likely to metastasize. The remaining chromosome 3 may have a mutation in the gene BAP1 that keeps it from being able to play its normal role of inhibiting tumor spread.

Testing for loss of chromosome 3 does not, however, carry very powerful predictive value. Much more precise is the gene expression test DecisionDx-UM, developed in the laboratory of Dr. J.W. Harbour at Washington University in St. Louis, Missouri, several years ago. The New York Times reported enthusiastically on the test in 2012, and it is effective at predicting metastasis most of the time. Other clinicians and researchers are trying to develop new tests that might work even better.

If the recent discoveries identifying verteroporfin as a new melanoma drug pan out in practice, patients at high risk of metastasis (identified through a precise predictive test) will be able to receive preventive treatment well before tumor cells remaining after initial treatment have a chance to lodge in the liver and, eventually, kill.




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