Melanoma of the eye (“uveal melanoma” – UM) is a rare tumor that originates from pigment-producing cells (melanocytes) in the eye. While UM is the most common primary eye malignancy in adults, it is rare compared to skin melanoma. Nearly one half of UM patients develop metastases that most often localize to the liver. Rapid tumor progression in the liver leads to death in 4 to 15 months. Metastatic UM (MUM) is highly resistant to chemotherapy. An alternative form of therapy called immunotherapy has also been explored in MUM. Immunotherapy activates the patient’s immune system to attack cancer cells in a targeted manner. While this approach has been very powerful in numerous contexts, and several drugs have already been approved by the US Food and Drug Administration, it has shown limited benefit for UM patients.

A new FDA-approved therapy for UM, Tebentafusp-tebn, is shown more promise. The therapy works by increasing the numbers of cancer-fighting cells and is currently the preferred treatment for 50% of Caucasians with MUM. Survival in patients receiving Tebentafusp-tebn was prolonged by approximately 6 months compared to standard care treatments. Response to treatment is typically evaluated through imaging. Imaging has its own challenges because of confounding factors. On the other hand, molecular markers that can gauge sensitively and specifically the response to treatment, and the speed of that response, could drastically improve the quality and speed of clinical decision making. In this project, we will explore a novel approach: we will develop biomarkers of response to treatment that are based on short non-coding RNAs (sncRNAs).

SncRNAs are important because they regulate the abundance of proteins, and, by extension, cell fate. Indeed, we now know that sncRNAs control numerous essential cellular processes, in health and disease. Advances during the last decade have demonstrated that the manner in which sncRNAs control proteins depends on tissue type and disease type. Thus, sncRNAs are very good candidates to serve as sensitive and specific diagnostic and prognostic tools, and this is why we chose them as the basis for this project.

The project has two parts. First, we will study liver tumors from MUM patients participating in a clinical trial at Jefferson. In these tumors, we will examine the levels of sncRNAs and of the RNA templates from which proteins are made. We will determine how these levels differ from what is seen in the primary tumors of UM patients who developed or did not develop metastases. We will determine how these levels change over time during treatment. Second, we will study sncRNAs in the blood of the same patients at different time points during treatment and determine how their levels differ from those in the blood of UM patients without metastases. We will determine how sncRNA blood levels change as treatment progresses and build a mathematical model to capture the speed of response to therapy. Once built, the model will allow us to accurately assess the response of patients while they are receiving the therapy.

Our short-term goal is to create biomarkers that leverage the power of sncRNAs in the MUM context. If successful, we expect to use the biomarkers in clinical settings to assist in clinical decision-making. Our long-term goal is to extend patient survival by creating novel targeted therapies for MUM. It is important to note that the methods we will develop in this project are very general in nature and can be used with other therapeutic regimens, and other cancers, where it is important to have molecular tests that accurately determine response to therapy in real-time.