Model-based prediction and experimental validation of novel therapeutic interventions for melanoma brain metastases
Despite tremendous advances in treating metastatic melanoma, most patients still die from brain metastases. Mutational landscapes of brain and non-brain metastases were found to be highly similar, but the observed epigenetic reprogramming of melanoma brain metastases is suspected to be a key mechanism involved in therapy resistance. An interdisciplinary multi-omics-driven approach is urgently needed to disentangle underlying driver genes, key pathways, and molecular mechanisms to develop novel therapeutic strategies for the targeted treatment of melanoma brain metastases. We have already measured epigenomes and transcriptomes of a world-wide unique cohort of patient-specific melanoma metastases pairs from brain and other organ sites enabling to reveal therapy-relevant differences at an unprecedented level. In MelBrainSys, we will implement a highly innovative systems medicine approach that integrates medical bioinformatics (Dr. Michael Seifert), dermatooncology (Dr. Dana Westphal), immunology (Dr. Rebekka Wehner), and neurooncology (Dr. Matthia A. Karreman) to computationally predict and experimentally validate new promising targets for the development of novel targeted therapeutic interventions. The role of the identified target genes in tumor growth, invasion and metastasis as well as their influence on the tumor immunogenicity and surrounding immune architecture will be analyzed in novel in vitro and in vivo melanoma model systems after CRISPR/Cas9-based manipulation of the targets. The resulting markers and phenotypic responses will be used to develop a model-based algorithm to predict potential efficiencies of targeted-perturbations for individual metastases coupled with validations in a mouse model system for melanoma brain metastases and a retrospective study. In summary, our consortium provides an excellent basis for the translational exploitation of systems-based predictions. Our long-term goal is to initiate a clinical trial with new brain-specific therapeutics for melanoma brain metastases.