Pilot Award Program

Targeting Metabolism to Induce Gasdermin-Mediated Inflammatory Cell Death in Uveal Melanoma

Advanced stage uveal melanoma often responds poorly to a number of therapeutic options including immunotherapy which helps the immune system to fight cancer. A type of immunotherapy called immune checkpoint inhibitors successfully treat a subset of patients with skin melanoma but patients with uveal melanoma respond poorly to these drugs in clinical trials. We predict that there is a lack of recognition of uveal melanoma tumors by the immune system. Our studies in skin melanoma found that a process that cancer cells undergo called pyroptosis, a type of inflammatory cell death, releases proteins from cancer cells that can attract the immune system to the cancer cells. A critical protein involved in pyroptosis called gasdermins are present in uveal melanoma. One way to enhance pyroptosis and activate the gasdermin proteins is by metabolic inhibitors; some of which have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of other diseases. We have data showing that a metabolic inhibitor causes pyroptosis in uveal melanoma cells. These cells were isolated from patient's tumor, grown as cultures, and should retain the majority of the tumor's characteristics. In this proposal, we will identify how metabolic inhibitors induce pyroptosis and which classes of metabolic inhibitors are capable of increasing pyroptosis. Importantly, we will determine whether metabolic inhibitors can enhance the efficacy of immune checkpoint therapy in uveal melanoma. Our findings will show a treatment strategy that potentially improves patient survival.

Generation and Optimization of Humanized Mice to Investigate Metastatic Uveal Melanoma Immunity

Melanoma of the eye, also known as uveal melanoma (UM), is a rare tumor that originates from pigment-producing cells (melanocytes) in the eye. Although rare, it is the most common primary intraocular malignancy in adults. During the past decade, substantial progress has been achieved in the treatment of primary eye lesions while preserving the affected eye. Even with appropriate treatments in primary UM, an estimated 40-50% of all patients will eventually die of metastatic disease. Systemic metastasis is most commonly found in the liver where tumors rapidly progress. Metastatic UM (MUM) is highly resistant to chemotherapy and inhibitors.

In the past decade, immunotherapy, a therapy in which the patient’s own immune system is activated to fight against cancer cells, has become a powerful approach to treat metastatic skin melanoma. Several immunotherapies were successfully tested in patients with metastatic skin melanoma. These medications improve overall survival of patients with skin melanoma and become a cure for patients. Unfortunately, these medications do not work well for MUM and only a limited number of MUM patients receive clinical benefit from them. Recently a new immunotherapy medicine, tebentafusp (Kimmtrak®), was approved by the FDA for the treatment of MUM patients. Although survival was prolonged, dramatic shrinkage of MUM was rare. Therefore, there is still an unmet need for better treatment for MUM patients.

Based on our and other researchers' data, we would like to further explore the reasons for the low responsiveness of MUM to immunotherapy. While researchers are able to study immune responses against skin melanoma using animal models, there are no animal models with immune systems to study UM, because of lack of mice with a UM cell line. Therefore, not enough research has been done to confirm our speculation. We have already developed an animal model of liver metastasis of UM that does not have an immune system. Our approach is to establish a mouse model with human immune cells (humanized mice). Using this model, we can study how tumors manipulate their microenvironment, how tumors enhance the anti-cancer drug resistance response, and how we induce the efficacy of immunotherapy against human MUM.

To achieve these goals, we proposed the following two projects in this pilot award application:

Aim 1: Generate humanized mouse model. Our primary aim is to develop a mouse model with human immune cells after transplantation of human hematopoietic stem cells obtained from healthy donors. We will study the induction of immune cells and functional assay.

Aim 2: Investigate immune system in humanized mouse with human MUM. This aim is to test the degree of immune attack to MUM after the transplant of the human hematopoietic stem cells into the mice.

Our long-term goals are to identify pharmacological approaches and to investigate effective immunotherapeutic drugs or combinational approaches with inhibitor(s) or chemotherapeutic drug(s) to achieve effective killing of MUM cells.