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Identification and validation of proteins and core signaling pathways associated with therapy resistance of melanoma brain metastases

Summary of the Project

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.

Scientific Goals

  • 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
Wordcloud copyright: Copyright Jason Davies | Privacy Policy. The generated word clouds may be used for any purpose. Immunohistochemical stainings copyright: To the project leaders and cooperation partners (Meier/Muders/Seifert/Westphal/Meinhardt) of the N

Figure: A) Wordcloud of the project. B) Immunohistochemical stainings of formalin-fixed paraffin-embedded melanoma brain and lung metastasis tissue of the same patient.

Wordcloud copyright: Copyright Jason Davies | Privacy Policy. The generated word clouds may be used for any purpose. Immunohistochemical stainings copyright: To the project leaders and cooperation partners (Meier/Muders/Seifert/Westphal/Meinhardt) of the NCT Proof of Concept Project “Identification of novel prognostic and predictive biomarkers in patients with melanoma brain metastases”

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Seifert M
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Niessner H, Schmitz J, Tabatabai G, Schmid AM, Calaminus C, Sinnberg T, Weide B, Eigentler TK, Garbe C, Schittek B, Quintanilla-Fend L, Bender B, Mai M, Praetorius C, Beissert S, Schackert G, Muders MH, Meinhardt M, Baretton GB, Dummer R, Flaherty K, Pichler BJ, Kulms D, Westphal D, Meier F. PI3K Pathway Inhibition Achieves Potent Antitumor Activity in Melanoma Brain Metastases In Vitro and In Vivo, Clin Cancer Res, 2016, 22(23), 5818-5828.

Seifert M, Friedrich B, Beyer A. Importance of rare copy number mutations for personalized tumor characterization and survival analysis, Genome Biology, 2016; 17:204.

Thiele S, Zimmer A, Göbel A, Rachner TD, Rother S, Fuessel S, Froehner M, Wirth MP, Muders MH, Baretton GB, Jakob F, Rauner M, Hofbauer LC. Role of WNT5A receptors FZD5 and RYK in prostate cancer cells, Oncotarget, 2018, 9(43), 27293-27304.

Contact

Prof. Friedegund Meier
Head Division of Experimental Dermato-Oncology and Skin Cancer Center,
Department of Dermatology, Carl Gustav Carus Faculty of Medicine at TU Dresden and University Hospital Dresden
Phone: +49 351 458 3677
Email: friedegund.meier(at)uniklinikum-dresden.de

Dr. Michael Seifert, Group Leader Bioinformatics Core Unit, Institute for Medical Informatics and Biometry (IMB), Carl Gustav Carus Faculty of Medicine at TU Dresden
Phone: +49 351 458 6056,
Email: michael.seifert(at)tu-dresden.de

Prof. Gustavo Baretton
Director Institute of Pathology, Carl Gustav Carus Faculty of Medicine at TU Dresden and University Hospital Dresden
Phone +49 351 458 3000,
Email: gustavo.baretton(at)uniklinikum-dresden.de