Melanoma is the third most common source of brain metastases (BM), exceeded only by lung and breast cancer. In addition, metastatic melanoma cells have the highest propensity for settling in the brain out of any solid tumor1. Melanoma also has one of the highest rates of leptomeningeal disease (LMD), which occurs when melanoma spreads to the cerebrospinal fluid (CSF) and the membranes that surround the brain and spinal cord. LMD is generally associated with a short survival of weeks to months2. With the advent of targeted drug therapy, checkpoint immunotherapy, cell-based therapy, and targeted radiation therapy, the median survival of patients with melanoma BM has improved but still only a subset of these patients respond to these treatments. For patients with LMD, improvements in survival from the new therapies show less impact. A high unmet medical need to identify new treatment options for patients with melanoma BM and LMD persists.
To improve outcomes for patients with melanoma BM and LMD, several important research areas are being explored. Characterizing the unique neurological environment that attracts and enables melanoma cells to grow in the brain and CSF is important to understand the high propensity for melanoma to spread to these tissues. Understanding biological distinctions between metastases to the brain and CSF compared to metastasis to other organs, like the liver or lungs, can also provide insight as to the uniqueness of BM and LMD. Finding ways to treat melanoma BMs when they first reach the brain and prevent them from growing are other avenues being actively explored. Identifying new targets to develop novel therapies and combination approaches and establishing the appropriate preclinical metastatic models for drug testing is also being extensively investigated. Furthermore, increasing enrollment of patients, especially with LMD and symptomatic BM, into clinical studies to test novel therapeutics is critical to advance clinical research of these diseases.
When melanoma cells enter the brain, they interact with multiple brain cell types including astrocytes (supporting cells in the central nervous system [CNS]), oligodendrocytes (cells in the CNS that make myelin), microglia (brain-resident macrophages), and a limited number of other immune cells. Melanoma cells must adapt to this unique environment to survive and grow. Research supported by MRA involves understanding this tumor microenvironment (TME) that is very different from other places in the body to figure out how to exploit unique vulnerabilities with therapies.
Patients who have brain metastases–with no neurologic symptoms (asymptomatic) and small tumors that are not in critical parts of the brain–may be treated with systemic therapy, especially the combination of the two immune checkpoint inhibitors, ipilimumab and nivolumab (encouraging overall survival results of the ABC clinical trial3). Patients with asymptomatic BMs are more likely to be included in clinical trials. However, the standard of care for patients with symptomatic BMs is not as clear and this patient population is less likely to be included in clinical studies. Preclinical work is focused on identifying new targets and therapies that would either boost the immune system’s ability to fight BMs or involve novel mechanisms and pathways to exploit therapeutically.
Melanoma has one of the highest incidences of LMD among solid tumors with a very poor overall survival measured in weeks to a few months. A major challenge in treating patients with LMD is getting a reliable diagnosis due to a lack of clear diagnostic and response criteria. In addition, the biology of LMD is fundamentally distinct from that of BMs and it occurs in a different neurological microenvironment (the CSF versus the brain). Current research is aiming to understand the factors that distinguish LMD from BM. Examples include:
Like melanoma, other cancers including breast and lung cancer have the highest rates and propensity for spreading to the brain and developing LMD. Sharing information between researchers who study BM and LMD in other cancer types can provide a potential source of new targets and shared mechanisms of how the brain and CSF microenvironments support metastatic growth. Furthermore, sharing preclinical models of brain metastasis or LMD across cancer types is also needed as there are not many faithful models of these diseases. MRA strives to facilitate and support collaborative studies with researchers across cancer indications.
1Redmer T. Deciphering mechanisms of brain metastasis in melanoma – the gist of the matter. Molecular Cancer (2018).
2Oliva IG, Schvartsman G, Tawbi H. Advances in the systemic treatment of melanoma brain metastases. Annals of Oncology (2018).
3Long GV, Atkinson V, Lo Stez JR, Knighton BG, Ledesma DA, Hudgens CW, Delcid YF, Hu Q, Onana CYB, Carapeto FCL, Tezlaff MT, Huse JT, Hwu P, Burton EM, Glitza Oliva IC, Davies MA, Ferguson SD. Preclinical models of melanoma leptomeningeal disease to assess intrathecal checkpoint blockade. Scientific Reports (2025).
4Guerrieri RA, Fischer GM, Cortez JR, Knighton BG, Ledesma DA, Hudgens CW, Delcid YF, Hu Q, Onana CYB, Carapeto FCL, Tezlaff MT, Huse JT, Hwu P, Burton EM, Glitza Oliva IC, Davies MA, Ferguson SD. Preclinical models of melanoma leptomeningeal disease to assess intrathecal checkpoint blockade. Scientific Reports (2025).
