CIRM-Funded Scientists Identify Cause; Potential Therapy for Deadly Form of Eye Cancer

If the cancer is caught early, you may just lose your eye. If it is caught too late, however, you may lose your life.

uch is the fate of those diagnosed with uveal melanoma, a rare but deadly form of eye cancer that attacks the eye’s pigment cells in the iris. Each year about 2,000 people are newly diagnosed with this condition, which often metastasizes into the liver. Once this happens, treatment is difficult. Patients with the metastasized form of uveal melanoma often die within a year.

Scientists have long observed that 70% of people with this form of cancer harbor the same two genetic changes, or mutations, in their DNA. They suspected that there was a link between these mutations and cancer, but until now had been unable to track one down.

Enter Dr. Kun-Ling Guan, pharmacology professor at the University of California, San Diego (UCSD) School of Medicine and the Moores Cancer Center. Reporting in the May 29 issue of the journal Cancer Cell, he and his UCSD team argue that they may have solved this long-standing mystery. As he eluded in last week’s news release:

“The genetics of this cancer are very simple and our results have clear implications for therapeutic treatments for the disease.”

In this study, Guan and his team focused on the two mutations associated with this cancer, called GNAQ and GNA11. Their experiments revealed that these two genes code for so-called “G-proteins” that normally regulate how information gets transmitted between cells. Normally, these proteins are switched on and off at specific intervals—and for a specific duration—in order to regulate the stream of information.

But mutations in these two genes shift the G-proteins into the “on” position—permanently. This creates a domino effect, whereby other proteins get activated when they shouldn’t be, such as a protein called YAP. With YAP on overdrive, pigment cells in the eye start multiplying unchecked, leading to the development of cancer.

Guan and his lab have been studying YAP as it relates to the growth of embryonic stem cells. He was recently awarded a CIRM Basic Biology II Grant to understand the protein’s role in stem cell growth and development. The discovery that overactive YAP is also implicated in such a deadly form of cancer offers new hope for developing therapies to treat the cancer and, importantly, save lives.

In fact, previous research by others revealed that the drug verteporfin, already FDA-approved to treat abnormal blood-vessel formation in the eye, can also block abnormal YAP activity, presenting a potential therapeutic strategy. In experiments on animal models genetically modified to mimic uveal melanoma, Guan and his team found that verteporfin does indeed suppress tumor growth.

These findings offer a concrete example of how a fundamental biological discovery can have real clinical applications. As Guan explained:

“We have a cancer that is caused by a very simple genetic mechanism. And we have a drug that works on this mechanism. The clinical applications are very direct.”

Anne Holden