Abstract
The development of brain metastases in patients with advanced stage melanoma is common, but the molecular mechanisms responsible for their development are poorly understood. Melanoma brain metastases cause significant morbidity and mortality and confer a poor prognosis; traditional therapies including whole brain radiation, stereotactic radiotherapy, or chemotherapy yield only modest increases in overall survival (OS) for these patients. While recently approved therapies have significantly improved OS in melanoma patients, only a small number of studies have investigated their efficacy in patients with brain metastases. Preliminary data suggest that some responses have been observed in intracranial lesions, which has sparked new clinical trials designed to evaluate the efficacy in melanoma patients with brain metastases. Simultaneously, recent advances in our understanding of the mechanisms of melanoma cell dissemination to the brain have revealed novel and potentially therapeutic targets. In this review, we provide an overview of newly discovered mechanisms of melanoma spread to the brain, discuss preclinical models that are being used to further our understanding of this deadly disease and provide an update of the current clinical trials for melanoma patients with brain metastases.
Highlights
Metastasis is a complex, multi-step process resulting in the spread of tumor cells from a primary lesion to a disparate organ or organs within the body, that results in increased patient morbidity and mortality [1]
These correlations suggest that changes in the intracranial “immunokine” profile may facilitate the establishment of brain metastases by melanoma cells through altered cytokine and receptor signaling that positively influences the retention or homing of disseminated melanoma cells to the brain
Buparlisib is able to cross the blood-brain barrier (BBB) and inhibited growth of melanoma brain metastases in nude mice [107]. These results are encouraging, many additional tests are required before buparlisib or other PI3K/AKT inhibitors can advance to clinical trials
Summary
Metastasis is a complex, multi-step process resulting in the spread of tumor cells from a primary lesion to a disparate organ or organs within the body, that results in increased patient morbidity and mortality [1]. Kienast et al noted that arrested cells were able to evacuate from their initial resting place and subsequently relocate to another site within the brain vasculature [9] This observation corroborates what other studies have shown—that disseminated melanoma cells can be directed to and/or selectively retained within the brain by external cues originating in the parenchymal milieu, such as chemokines or brain-derived ligands. Lok et al observed a significant correlation between poor clinical outcomes and alterations in several CCR4-binding immunokines, including CCL22, CCL4, and CCL17 [24] These correlations suggest that changes in the intracranial “immunokine” profile may facilitate the establishment of brain metastases by melanoma cells through altered cytokine and receptor signaling that positively influences the retention or homing of disseminated melanoma cells to the brain. Once localized within the brain, melanoma cells receive tissue-derived cues that potentiate extravasation, the transmigration of metastasizing cells out of the vasculature and across the BBB
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