Calcineurin-NFAT Axis Is a Potential Therapeutic Target for Uveal Melanoma Metastasis
Abstract
Uveal melanoma is the most common primary cancer of the eye. The major cause of death in uveal melanoma patients is the spread or metastasis of the cancer to other vital organs such as the liver. Although most patients do not show signs of metastasis at the time of diagnosis, eventually about 50% of patients will develop metastatic disease, which is almost invariably fatal. Over 90% of uveal melanomas possess a mutation in one of two similar G alpha q genes, known as GNAQ and GNA11. There are many studies demonstrating that mutations in GNAQ or GNA11 drive the formation and growth of the tumors. It has been shown that the activation of a particular protein known as ARF6 by mutant GNAQ controls all of the known signaling pathways that are involved in uveal melanoma formation and growth. However, the molecular mechanisms that govern how uveal melanoma cells are disseminated and grow at distant sites remains unknown. Given that metastasis of the cancer is the primary cause of death, it is very important to identify the molecular basis for this process. Growth factors, such as hepatocyte growth factor (HGF) and insulin-like growth factor 1 (IGF1) have been implicated in uveal melanoma liver metastasis, and we have recently found that these growth factors activate an ARF6-calcineurin-NFAT signaling pathway, which appears to promote uveal melanoma cell spreading and metastasis. Therefore, we hypothesize that this novel molecular pathway is essential for uveal melanoma metastasis and that inhibiting this pathway would reduce metastatic disease. Importantly, there are several known pharmacologic inhibitors of key components of this pathway, including two calcineurin inhibitors that are already Food and Drug Administration (FDA)-approved for other indications. Our experiments are designed to establish the roles of ARF6, calcineurin, and NFAT in uveal melanoma metastasis. During the course of these experiments, we will be testing the function of this signaling pathway by inhibiting its activation using different inhibitors that target ARF6, calcineurin, or NFAT individually. If our experiments are successful and we show that this pathway plays a critical role in uveal melanoma metastasis, we will have identified several potential therapeutic targets for this disease, many of which already have FDA-approved drugs targeting them, which might lead to effective therapies for this deadly cancer. Therefore, our study addresses two Focus Areas of the FY19 MRP: Rare Melanomas (Uveal Melanoma) and Therapeutic prevention (Interruption of Disease Progression).
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010935
Entities
People
- Jae Hyuk Yoo
Organizations
- United States Army
- University of Utah