Melanoma is the third most common malignancy to metastasize to the brain. It is estimated that at least 50% of patients with stage IV melanoma will develop brain metastases during the course of disease. There is now abundant evidence that some of the most common treatment options for non-resectable melanoma brain metastases, such as radiotherapy and targeted therapies, fail to confer complete responses in patients and offer little to no benefit for survival. A common reason for the failure of radiotherapy and anticancer drugs in patients with melanoma brain metastases is due to presence of therapy resistant cancer cells within the tumor. One of the driving forces that creates these resistant cell populations in the tumor is the constant state of stress that melanoma cells are exposed to in the tumor microenvironment. Melanoma cells must adapt to cope and survive these harsh and unhospitable conditions in the tumor. The consequence of this is the emergence of melanoma cells that are more aggressive and more resistant to treatment.

In our proposal, we describe a metabolic pathway that supports cancer cell survival during these episodes of stress in the tumor. Indeed, the enzymes we propose to target are involved in supporting melanoma tumor growth and promoting the transition to a more aggressive and resistant state during stress. We propose that targeting these enzymes will help prevent metastasis to the brain and help to treat patients with existing melanoma brain metastases. Since melanoma brain metastases are currently associated with dismal survival rates, our studies have the potential to address a significant unmet clinical need. We expect the proposed studies to advance the translation of our findings to the clinic and help reduce melanoma brain metastasis disparities.