Application of a DNp73-IGF1R signaling-based systems model for the prediction of metastasis probability and therapy responses in malignant melanoma

Our group provided first functional evidence that oncogenic DNp73 variants are crucial to initiate BRAF/NRAS/p53mut-independent melanoma invasion via the EPLIN-IGF1R/AKT axis, and identified a multilevel DNp73-governed regulatory network that specifically controls malignant progression. This opens up completely new possibilities for the treatment of aggressive melanoma. Due to the DNp73-network complexity, holding multiple overlapping nonlinear regulatory motifs, we apply a computational systems model to determine molecular fingerprints allowing patient-stratified therapies and the discovery of novel drug targets. For this purpose, we developed a mathematical model that allows to consider the interpatient heterogeneity for metastasis-targeted strategiesto generate molecular signatures reflecting early metastatic spread and drug resistance. Based on validated simulated signatures, we will design multimodal patient-tailored therapies using CRISPR-Cas9 knockout/activation strategies, in vivo LNAs, miR-mimics and clinically applied kinase inhibitors, which will be tested in established mouse metastasis models. The overall goal of this project is to provide DNp73-driven biomarker constellations that predict metastasis initiation and resistance probabilities, and to develop novel individual treatment paradigms.

Applicant

Prof. Brigitte Pützer M.D., Ph.D.
Rostock University Medical Center
Institute of Experimental Gene Therapy and Cancer Research

Research Partners

Prof. Jens Timmer Ph.D.
Faculty of Mathematics and Physics
BIOSS Centre for Biological Signaling Studies
Institute of Physics
Freiburg im Breisgau

PD Friederike Egberts M.D.
University Hospital Schleswig-Holstein, Campus Kiel
Department of Dermatology

This project is funded by the German Cancer Aid (Deutsche Krebshilfe) 70112353.

Contact

Institute of Experimental Gene Therapy and Cancer Research
Core-Facility Viral Vector & Genome-Editing Technologies
Biomedical Research Center
Schillingallee 69
D-18057 Rostock

Office

    (+49) 381 494-5066
    (+49) 381 494-5062
    ingrid.winkler@med.uni-rostock.de
Department Life, Light & Matter
Research Building LL & M
Albert-Einstein-Str. 25
D-18059 Rostock
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