Multimodal GNAQ Signaling: Precision Therapy for Metastatic Uveal Melanoma Prevention and Treatment

FY20 MRP Focus Area:

(1) The MRP encourages studies for rare melanomas across the entire spectrum from initiation to distant macro-metastasis. Our proposal investigates uveal melanoma, the second most prevalent site of melanoma development after the skin, with emphasis on prevention and treatment of distant macrometastasis.

(2) Therapeutic Prevention: Our studies will lead to a novel chemopreventive strategy to halt metastatic uveal melanoma development from their dormant liver lesions.

Scientific Objective and Rationale: Uveal melanoma is the most common primary cancer of the eye in adults, and is the second most common melanoma subtype after skin cutaneous melanoma. It is diagnosed in about 2,500 adults in the United States every year. Approximately 50% of uveal melanoma patients develop liver metastasis within 5-10 years after diagnosis, independently of the successful treatment of the primary lesions. Patients with large tumors that cannot be fully resected by surgery or with primary lesion relapse are at further risk for metastasis. Remarkably, this indicates that micrometastatic lesions in the liver can remain dormant for years after treatment of the primary tumor; however, once active, metastatic uveal melanoma patients are refractory to current chemotherapies and new immunotherapies, leading to rapid patient death within a year. Indeed, to date, there are no effective treatment options for metastatic uveal melanoma. Thus, there is large and urgent unmet need to develop new treatment strategies for thousands of patients at risk of developing metastatic uveal melanoma, and for the identification of novel effective therapies for metastatic uveal melanoma patients that will otherwise inexorably succumb to the disease in only few weeks or months.

A clear difference with skin melanoma is that most uveal melanoma lesions are driven by a particular cancer-causing gene known as GNAQ, often referred to as the GNAQ-oncogene, which also contributes to approximately 4% of skin melanomas. The ability of this oncogene to promote cancerous growth was initially discovered by one of the applicants of the team in the early 90s, and the large body of scientific information generated over the years by the team can now be deployed for identifying druggable mechanisms in uveal melanoma. Specifically, the team has been using state-of-the art unbiased large scale genetic and bioinformatics (computational) screens to understand why GNAQ causes cancer, aiming at developing new therapeutic avenues. These efforts led to the discovery of a new mechanism of cancer initiation that can explain why prior clinical studies have failed to change the natural progression of the disease, and new drug targets and drug combination approaches that can be quickly translated into the clinic for the treatment of metastatic uveal melanoma.

In parallel, the team has identified a suitable option to halt the progression of small and dormant liver uveal melanoma lesions into aggressive and rapidly lethal liver metastatic disease. They have recently discovered that metformin, a well-tolerated and Food and Drug Administration-approved oral antidiabetic drug, halts uveal melanoma growth. Metformin is the most widely used oral antidiabetic drug and is prescribed to at least 120 million people worldwide. Hence, metformin's safety profile for long term use and the management of its potential side effects are well documented.

The overall hypothesis of the studies is that the high specificity of GNAQ as a driver oncogene in uveal melanoma may represent a vulnerability that can be exploited for the development of new precision therapies for metastatic uveal melanoma prevention and treatment. The objectives are to exploit GNAQ-regulated oncogenic networks to develop precision therapies to treat metastatic uveal melanoma patients, and to target these networks with metformin as novel chemopreventive approach to halt the onset of fulminant metastatic liver disease.

Applicability of the Research: Our studies will lead to the development of the first combination precision therapy for metastatic uveal melanoma patients, and the use of metformin as a safe, effective, and low cost chemopreventive strategy to halt metastatic uveal melanoma development from their dormant liver lesions in thousands of high-risk uveal melanoma patients. Regarding treatment options, we will use a combination treatment of two drugs targeting a protein known as FAK and another known as MEK. This combination has been recently used in a clinical trial in multiple cancer types with acceptable toxicities and promising activity. Indeed, based on our studies, a clinical trial using this combination in metastatic uveal melanoma has been submitted at Jefferson University and University of California San Diego, where two of the leaders of the research team are located. This investigator-initiated and industry-sponsored trial is expected to open by December 2020. The current proposal will provide the framework for identifying metastatic uveal melanoma patients that will benefit the most from this novel treatment option. Similarly, the University of California San Diego investigator has recently completed a clinical trial using metformin for head and neck cancer prevention. Based on the results of the planned studies, this widely used antidiabetic agent can be quickly repurposed to prevent metastasis development in 50% of uveal melanoma patients at high risk for metastatic disease. Overall, the success of our proposed studies will rapidly achieve a patient-related outcome for uveal melanoma prevention and treatment.