Melanoma brain metastases remain the leading cause of skin cancer-related deaths, despite new effective therapy options for patients with metastatic melanoma. Although current therapies achieve similar initial response rates in brain and non-brain metastases, the majority of patients die from progressing brain metastases, indicating brain-specific resistance mechanisms. The genomic landscape of brain and non-brain metastases was found to be highly similar, but epigenetic reprogramming of brain metastases facilitated by the brain microenvironment was observed. To disentangle molecular mechanisms involved in therapy resistance, we have acquired the DNA methylation and gene expression status of patient-specific brain and matched non-brain metastases in a world-wide unique cohort of melanoma patients. The data showed significant differences in promoter methylation and corresponding gene expression between all brain and non-brain samples irrespective of pairing. A sub-set of promising candidates from these analyses was validated by immunohistochemistry. In addition, we also found that each matched pair has many additional DNA methylation and expression changes that may influence treatment response. We will thus perform an extended bioinformatics analysis of the methylome and transcriptome data of the matched pairs to derive gene candidates and key pathways associated with therapy resistance. Candidates from the bioinformatics analyses will be validated by wet-lab experiments to identify new patient-specific therapeutic targets for melanoma brain metastases.
- Identify candidate genes and key pathways associated with melanoma brain metastases using extended computational analyses of patient-specific melanoma metastasis pairs (brain vs. non-brain)
- Validate candidates in patient material and functional in vitro assays to elucidate their role in cellular processes such as apoptosis, tumor proliferation, migration and invasion
- Ultimately appoint new therapeutic targets for melanoma brain metastases