Identifying Novel Therapeutic Strategies for Metastatic Uveal Melanoma
Abstract
Uveal melanoma (UM) is a cancer arising from ocular melanocytes, the pigment cells in the eye. Metastasis is the spread of tumor cells to other locations of patient’s body. About 50% of UM patients develop metastatic, mainly to the liver and die of their disease. Despite dramatic successes in other melanoma subtypes, both immune and targeted therapies have been largely ineffective in UM. Animal models that accurately recapitulate the clinically relevant features of UM, in particular that of liver metastasis, are needed to help identify and prioritize effective treatment strategies to guide future clinical trials for this devastating disease. Over 90% of UMs harbor mutations in two closely related genes GNAQ and GNA11, which differ from mutations in other forms of melanoma. Less than 10% of UMs that do not have GNAQ or GNA11 mutations harbor recurrent mutations in CYSLTR2 or in PLCB4, both acting in the same cellular signaling pathway as GNAQ and GNA11. The mutant genes cause UM by driving uncontrolled tumor cell proliferation leading to tumor growth. Slight variation among the mutations in these genes result in differences in signaling and responses to the drug treatment. In order to develop precision medicine to treat UM patients, animal models that represent the most common combinations of mutations are needed to test therapeutic intervention and promote the most promising to clinical trials in patients. We have developed a mouse model that genetically engineered the GNAQ into melanocytes. These mice develop UM. As in humans, the GNAQ mutation is not sufficient to make melanoma cells metastatic. A second mutation in the tumor suppressor gene BAP1 is what typically causes GNAQ mutant tumor cells to development metastases, mainly to the liver. In Aim 1 of our proposal, we will develop a mouse model that has an intact immune system and develops liver metastases of UM. For this we will breed our GNAQ mice to BAP1 knock-out mice. In parallel, we are developing mouse models using human UM cells. We already have developed one model with the most common mutation in GNAQ and will use our expertise to establish similar models for other clinically relevant driver mutants including GNA11, CYSLTR2, and PLCB4, thereby creating models for the main combination of mutations seen in human UM. An additional goal of our proposal is to fill in details of oncogenic GNAQ and GNA11 signaling to look for additional opportunities to kill cancer cells or stop them from growing. We surveyed all genes in UM cells to determine which ones become activated and which ones are required for cells to survive. We found that the MYC and MTOR signaling pathways as downstream of mutant GNAQ/11. In Aim 2 of our proposal, we will evaluate these pathways as potential therapeutic target for UM using cellular models and the mouse models we develop. Our goal is to develop effective therapeutic strategies for metastatic UM. Expected deliverables from our work are new pre-clinical models that can be used to inform future clinical trials and, hopefully, additional therapeutic targets and strategies for patients. This proposal addresses all three Fiscal Year 2021 Rare Cancers Research Program Focus Areas of research model, therapy, and biology and etiology.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211068
Entities
People
- Xu Chen
Organizations
- United States Army
- University of California, San Francisco