Patients with advanced melanoma who develop metastases in the leptomeninges usually have a poor prognosis—most patients only survive for 8 to 10 weeks after diagnosis. One reason for this poor prognosis is that very little is known about the molecular development of leptomeningeal melanoma metastases, making it difficult to develop effective therapies. A research team sought to fill in some of this missing information by performing an extensive analysis of the molecular characteristics of the cerebrospinal fluid of patients with leptomeningeal melanoma metastases. Their findings were published by Smalley et al in Clinical Cancer Research.

Methods and Findings

The team wanted to improve their understanding of the development of leptomeningeal melanoma metastases leptomeningeal melanoma metastases by analyzing the protein and RNA composition of cerebrospinal fluid from patients. They compared the molecular profiles of eight control patients without leptomeningeal melanoma metastases to eight patients with leptomeningeal melanoma metastases, including one patient with metastases who had an extraordinary response to treatment and was still alive more than 35 months after diagnosis. 

They discovered that the cerebrospinal fluid from patients with leptomeningeal melanoma metastases was enriched for proteins involved in innate immunity, proteases, and the insulin-like growth factor (IGF)-signaling pathway. The most commonly altered protein was transforming growth factor (TGF)-β1. The patient who had an extraordinary response to treatment displayed high levels of these proteins at baseline, but expression levels decreased as the patient responded to treatment. However, the protein expression patterns in the remaining patients with leptomeningeal melanoma metastases who had poor responses to treatment were high at baseline and remained high throughout treatment and disease progression.

Researchers hypothesized that the cerebrospinal fluid of patients with leptomeningeal melanoma metastases could impact melanoma cells by modulating their molecular profile. They confirmed this hypothesis by incubating cerebrospinal fluid from the patients with leptomeningeal melanoma metastases with melanoma cells and discovered that the fluid was able to induce activation of proteins and signaling pathways involved in malignant progression, including the PI3K/AKT pathway, integrins, B-cell signaling, mitotic cell-cycle progression, tumor necrosis factor receptor (TNFR), TGF-β, and oxidative stress.

Their findings demonstrate that the cerebrospinal fluid from patients with leptomeningeal melanoma metastases who did not respond to treatment promoted survival of melanoma cells, while the cerebrospinal fluid from the extraordinary responder did not promote survival. These observations suggest that molecules exist within the cerebrospinal fluid that can stimulate melanoma cell survival and prevent cell death. The researchers reported that one of these survival molecules is TGF-β. The patient who responded well to treatment had very low to undetectable levels of cerebrospinal fluid TGF-β, whereas patients who did not respond to treatment had much higher levels of TGF-β.

The researchers hope that their data will provide important knowledge about leptomeningeal melanoma metastases and offer insights into potential therapeutic targets. “It is likely that the environment of leptomeningeal melanoma metastases is a key regulator of both disease progression and therapeutic response. Improved knowledge about the microenvironment of leptomeningeal melanoma metastases may allow novel therapeutic strategies to be developed that can delay disease progression,” concluded senior study author Kieran S.M. Smalley, PhD.

Disclosure: This study was supported by grants from the National Institutes of Health, the Department of Defense, and the State of Florida. For full disclosures of the study authors, visit clincancerres.aacrjournals.org.