Header Forschung

Identification of novel prognostic and predictive biomarkers in patients with melanoma brain metastases (cooperation project between NCT Dresden and NCT Heidelberg)

Summary of the Project

Up to 75% of stage IV melanoma patients develop brain metastases during the course of their disease. Brain metastases are associated with a median overall survival of only 3-6 months. Although there is concordance in the mutational landscape of intra- and extracerebral metastases, patients with brain metastases do not sufficiently respond to most therapies. This indicates specific resistance mechanisms.

To identify new prognostic and predictive biomarkers and to uncover mechanisms responsible for the different biological behavior in melanoma brain metastases, we have already established a worldwide unique cohort of 27 pairs of intra- and extracranial metastases with a complete clinical follow up as well as 40 melanoma intracerebral metastases for validation. In order to identify proteins and pathways that are responsible for the different biological behavior, we will
(1) identify differences in epigenetic modifications of genes by executing an Illumina 450k methylation array.
(2) simultaneously characterize differences in messenger RNA expression executing RNA-Seq by using the Illumina TruSeq RNA Access-protocol.
(3) validate identified differences in gene modification/messenger RNA expression and signaling pathways by conventional immunohistochemistry and correlation with clinical outcome.
(4) execute functional in vitro experiments that include standard cell culture methods to elucidate differences in survival, apoptosis, autophagy, cell cycle, migration, invasion, and colony formation.

Scientific Goals

  • Define target proteins and pathways that are associated with treatment resistance in melanoma brain metastases and can be used for further in vivo experimental and clinical studies.
  • Discover new prognostic markers as well as novel molecular targets for future therapeutic approaches to treat melanoma patients with brain metastases.

Niessner H, Forschner A, Klumpp B, Honegger JB, Witte M, Bornemann A, Dummer R, Adam A, Bauer J, Tabatabai G, Flaherty K, Sinnberg T, Beck D, Leiter U, Mauch C, Roesch A, Weide B, Eigentler T, Schadendorf D, Garbe C, Kulms D, Quintanilla-Martinez L, Meier F. Targeting hyperactivation of the AKT survival pathway to overcome therapy resistance of melanoma brain metastases. Cancer Medicine 2013; 2: 76-85

Beck D, Niessner H, Smalley KSM, Flaherty K, Paraiso KHT, Busch C, Sinnberg T, Vasseur S, Iovanna JL, Drießen S, Stork B, Wesselborg S, Schaller M, Biedermann T, Bauer J, Lasithiotakis K, Weide B, Eberle J, Schittek B, Schadendorf D, Garbe C, Kulms D, Meier F. Vemurafenib potently induces endoplasmic reticulum stress–mediated apoptosis in BRAFV600E melanoma cells. Sci Signal 2013; Jan 29;6(260):ra7. doi: 10.1126/scisignal.2003057.

Paraiso KH, Das Thakur M, Fang B, Koomen JM, Fedorenko IV, John JK, Tsao H, Flaherty KT, Sondak VK, Messina JL, Pasquale EB, Villagra A, Rao UN, Kirkwood JM, Meier F, Sloot S, Gibney GT, Stuart D, Tawbi H, Smalley KS. Ligand independent EphA2 signaling drives the adoption of a targeted therapy-mediated metastatic melanoma phenotype. Cancer Discovery 2014; doi:10.1158/2159-8290.CD-14-0293

Niessner H, Schmitz J, Tabatabai G, Schmid A, Calaminus C, Sinnberg T, Weide B, Eigentler TK, Garbe C, Shittek B, Quintanille-Fend L, Bender B, Mai M, Praetroius C, Beissert S, Schackert G, Muders M, Meinhardt M, Baretton GB, Dummer R, Flaherty KT, Pichler BJ, Kulms D, Westphal D*, Meier F* (2016) PI3K pathway inhibition achieves potent antitumor activity in melanoma brain metastases in vitro and in vivo. Clin Cancer Res 22 (2016) 5818-5828, *authors contributed equally

Westphal D*, Glitza Oliva I, Niessner H* (2017) Molecular insights in melanoma brain metastases. Cancer, in press, *authors contributed equally

Contact

Prof. Dr. med. Friedegund Meier
Department of Dermatology, University Hospital Dresden, TU Dresden
Phone: +49 (0)351 458 3677
Email: friedegund.meier(at)uniklinkum-dresden.de

PD Dr. med. Michael Muders
Department of Pathology, University Hospital Dresden, TU Dresden
Phone +49 (0)351 458 3041
Email: michael.muders(at)uniklinikum-dresden.de

Michael Seifert, PhD
Institute for Medical Informatics and Biometry (IMB), Medical Faculty, TU Dresden
Phone +49 (0)351 458 6056
Email: michael.seifert(at)tu-dresden.de