In vivo Modeling and Molecular Characterization: A Path Toward Targeted Therapy of Melanoma Brain Metastasis

Abstract

Brain metastasis (B-Met) from melanoma remains mostly incurable and the main cause of death from the disease. Early stage clinical trials and case studies show some promise for targeted therapies in the treatment of melanoma B-Met. However, the progression-free survival for currently available therapies, although significantly improved, is still very short. The development of new potent agents to eradicate melanoma B-Met relies on the elucidation of the molecular mechanisms that allow melanoma cells to reach and colonize the brain. The discovery of such mechanisms depends heavily on pre-clinical models that enable the testing of candidate factors and therapeutic agents in vivo. In this review we summarize the effects of available targeted therapies on melanoma B-Met in the clinic. We provide an overview of existing pre-clinical models to study the disease and discuss specific molecules and mechanisms reported to modulate different aspects of melanoma B-Met and finally, by integrating both clinical and basic data, we summarize both opportunities and challenges currently presented to researchers in the field.

Melanoma central nervous system metastases: current approaches, challenges, and opportunities

“…While these models have provided a wealth of information, a major obstacle in studying MBM has been the lack of animal models that mimic the pattern of metastasis observed in human disease. To circumvent this limitation, several groups have employed experimental models in which human cells have been introduced into the brain via direct intracranial injection or into the CNS circulation via intracarotid or intracardiac injection (Gaziel‐Sovran et al., ). Interestingly, data exist that melanoma cell lines may form different patterns of CNS metastases following such procedures.…”

RNA Sequencing Analysis Reveals Interactions between Breast Cancer or Melanoma Cells and the Tissue Microenvironment during Brain Metastasis

“…Such analyses of human brain metastasis have contributed to the identification of predictive markers as well as providing a basis for the development of novel therapeutic targets [ 6 , 7 ]. Analysis of mouse experimental models has identified several genes that mediate the metastasis of breast cancer and melanoma cells to the brain [ 8 , 9 ]. Extracellular vesicles, or exosomes, released by cancer cells have also been found to promote metastasis in an organ-specific manner [ 10 , 11 ].…”

HGF/MET Signaling in Malignant Brain Tumors

“…Despite the use of various combinations of treatments such as surgery and radiotherapy, brain metastases are very difficult to treat. The response rates to single-agent chemotherapy are less than 10%, and treatment only slows but does not arrest or reverse disease progression [ 106 ]. It is becoming clear that the genetic background of a certain patient or a tumor should dictate its treatment regimen, and that targeted therapy against these tumor-specific alterations may be more efficacious (discussed in the next section) [ 106 ].…”