Strategy to Target Acquired Resistance in MelanomaBrainMets

Brain metastases develop from tumor cells that enter the brain via the bloodstream at a certain point in time. Unlike primary brain tumors, which develop from brain cells, brain metastases stem from tumors outside the brain. Melanoma cells (black skin cancer) that have entered the brain can remain undetected and dormant for years. In 40-60% of melanoma patients, these dormant micrometastases develop into symptomatic and life-threatening tumors. Despite an initially good response to currently available first-line therapies such as targeted blocking (BRAF inhibitors, BRAFi) of the overactivation of BRAF kinase caused by mutations, brain metastases continue to pose a major challenge. Primary tumors and brain metastases do not represent uniform tissues, but are highly heterogeneous and comprise a variety of different tumor cell types that can develop individually and respond differently to therapeutic measures. Therapeutic measures can influence this development and drive the formation of resistant tumor cells. The STAR-MBM (Strategy to Target Acquired Resistance in Melanoma Brain Metastases) project, will decipher the spatial heterogeneity of brain metastases in melanoma patients. We will investigate how the spatial interaction of tumor cells with surrounding cells, such as astrocytes and macrophages, leads to activation of the MET receptor in therapy (BRAFi)-resistant tumors. The MET receptor is a molecule that controls the growth and spread (infiltration) of tumor cells and therefore represents a promising therapeutic target. Through exome sequencing of therapeutically naive or responsive and resistant brain metastases, we will be able to identify mutations that are potentially associated with therapy resistance for the first time. Using cell culture models and preclinical brain tumor models, we will further test therapeutically relevant inhibitors of the MET receptor (METi) in synergy with BRAFi. Integrated analysis of the data will provide more detailed insights into the spatial landscapes of therapy-resistant brain metastases and enable the development of an in silico model of spatial therapy resistance for the identification of potential biomarkers. Our promising study will be the first to use spatial transcriptome analysis to elucidate resistance mechanisms in brain metastases of melanoma. Furthermore, our project will determine the effectiveness and safety of METi as a potential second-line therapy for patients with acquired resistance to BRAFi, thereby making an important contribution to improving treatment options for melanoma patients with brain metastases.