CURE Ocular Melanoma (CURE OM) awards grant to develop treatments for uveal melanoma

A research team directed by Professors John Sondek, PhD, UNC School of Medicine and William Janzen, UNC Eshelman School of Pharmacy, has been awarded a two-year grant from the Community United for Research and Education of Ocular Melanoma (CURE OM) to identify inhibitors of an oncogene found in the majority of melanomas of the eye.

G proteins are molecular switches: they have “off” and “on” states. Normally, these proteins are off until activated by G protein-coupled receptors. Drs. Brian Kobilka and Robert Lefkowitz shared the 2012 Nobel Prize in Chemistry for describing how G protein-coupled receptors activate G proteins in order to move information from the outside of cells to their interior. When G proteins are on, they directly bind and change other proteins inside of the cell. This leads to a wide range of cellular responses including cell growth, movement and division as well as communication between cells.

What happens if a G protein is always on? The outcome is often tragic. For example, in approximately 80% of the cases of uveal melanoma, either of two closely related G proteins, Galpha-q and Galpha-11 (gene names GNAQ and GNA11) are mutated so that they cannot shut off.  These mutations “drive” these melanomas and are referred to as driver mutations since they promote these cancers.  However, knowing that these mutated G proteins often lead to uveal melanoma is only the first step toward a treatment. How can we use this knowledge to help patients with uveal melanoma?

In the Sondek lab, we’ve focused on improving our understanding of how the movement of information controlled by G proteins is regulated. In a 2010 paper published in the journal Science, we showed how an activated G protein, Galpha-q in the on state, interacts with one of its primary molecular targets within the cell by determining the structure of the two molecules bound together at atomic resolution. This structure is a 3-D roadmap for how to prevent the G proteins with driver mutations found in most cases of uveal melanoma from communicating with their molecular targets.

We know that certain mutated G proteins found in the eye can result in uveal melanoma and we have a model for how to prevent these mutated G proteins from communicating with their targets. And yet there’s still a long way to go before this knowledge can help treat patients with uveal melanoma. Fortunately, a postdoctoral fellow in the Sondek lab, Dr. Thomas Charpentier, was inspired by this work to develop that next step that will help take us from the laboratory to clinical application. Dr. Charpentier devised a method to measure the interaction of Galpha-q in the on state with its molecular targets.  He adapted this method so that it works with exceptionally small amounts of protein and with hundreds of samples at a time. We are now collaborating with Prof. Bill Janzen and the UNC Center for Integrative Chemical Biology and Drug Discovery to screen their collection of 100,000 small molecules for ones that prevent the mutated G proteins from communicating with their targets. We intend to turn the molecules we find into effective drugs for the treatment of uveal melanoma.

This exciting and potentially life-saving work was stalled due to a lack of funds. We are grateful to CURE OM and the Melanoma Research Foundation for the opportunity to continue this work in the ongoing effort to eliminate uveal melanoma and save lives.