TP B.4 - MelBrainSys

In vivo validation of therapeutic targets inhibiting melanoma brain metastases growth

Established therapies against melanoma brain metastasis often show only limited or short-term effects. This can be attributed to the unique nature of the brain-microenvironment and underscores the need to find novel brain-specific therapies. Since in vitro models not fully recapitulate the complexity of the living brain, clinically relevant in vivo models are required to identify and test therapeutic strategies. The aim of this subproject is to in vivo validate and study the candidates for brain-specific therapeutic targets, which are identified in subproject B.1 using multi-omics screens and experimentally validated in subprojects B.2 and B.3. Hereto, we will first develop new in vivo models of melanoma brain metastasis using the primary, patient-derived, brain melanoma cell lines established in subproject B2. Using a unique microscopy technique, we can visualize the primary melanoma cells in the brain of a living mouse, and study how the metastases grow in vivo. The effect of manipulation of the target genes (B.1, B.2) on brain metastatic growth will then be characterized in our in vivo model. The results of these studies will be fed back into the computational models (B.1), enabling to improve the prediction of response to targeted therapies to candidates. This then allows defining our therapeutic strategies (B.1-B.3), which will be tested as part of this project on further cell lines using in vitro and in vivo studies. The overall goal of this project is to formulate a novel treatment protocol for patients suffering from melanoma brain metastasis.