KFO 216:  Characterisation of the Oncogenic Signalling Network in Multiple Myeloma: Development of Targeted Therapies

• Subject Area: Medicine
• Term: from 2009 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 100308792

The underlying hypothesis for the Clinical Research Unit is the assumption that in multiple myeloma the malignant phenotype results from deregulation not of a single but of a number of signalling pathways, and that these collectively constitute an oncogenic signalling network. Consequently, we assume that differences in this network may permit functional definition of novel subgroups of this disease.
It is therefore the aim of this Clinical Research Unit to attempt an extensive functional characterisation of the oncogenic signalling network to permit the development of novel and effective therapeutic options. This aim will be pursued via two complementing methodical approaches: (1) a combination of functional, molecular and genetic ex vivo characterisations of primary myeloma cells, and (2) the development of different genetic mouse models to study and to verify the oncogenic pathways in primary human myeloma samples in vivo. These animal models will eventually serve in preclinical studies of novel therapeutic approaches.
Our previous work has led to the identification of a number of signalling systems that are activated in myeloma cells, such as Ras-, NF-kB- and stress-response-pathways (e.g. the heat shock protein pathway). Our aim is to appraise the functional importance of these pathways in myeloma as accurately as possible and to analyse if and to what extent they cooperate with each other. In a complementary approach we plan to screen for still unknown signalling pathways by using shRNA-based screening techniques.
Finally, we will try to identify the genetic lesions that might lead to the activation of these pathways. To this end, we will apply novel genetic technologies such as for example high-throughput sequencing. The results should help to obtain a better understanding of the functional and molecular heterogeneity of this disease. They should also promote identification of novel therapeutically relevant targets and implementation of novel treatment approaches that may be designed to specifically target suitable myeloma subgroups.
Within the framework of this Clinical Research Unit, 20 scientists from six different institutes of Wuerzburg University cooperate in six subprojects and three core facilities (z-projects). There is also a close cooperation with physicians and scientists from the department of internal medicine II at the Ulm University.

• DFG Programme: Clinical Research Units

Projects

• Administration of the Clinical Reasearch Unit (Applicant Bargou, Ralf C. )
• Central facility for mass spectrometry and proteomics (Applicant Schlosser, Andreas )
• Centralized sample preparation, pathology and preclinical in vivo models (Applicants Beilhack, Andreas ;  Einsele, Hermann ;  Rosenwald, Andreas )
• Characterization of RAS-dependent effector signaling pathways in multiple myeloma (Applicants Bargou, Ralf C. ;  Chatterjee, Manik ;  Steinbrunn, Torsten )
• Clinical and molecular characterization of newly detected mutations in receptor tyrosine kinases, adhesion molecules and their downstream effectors (Applicants Leich-Zbat, Ellen ;  Rosenwald, Andreas )
• Core facility for molecular cytogenetics, genetic diagnostics and profiling (Applicants Bullinger, Lars ;  Langer, Christian )
• Design, characterization and optimization of HSP70 inhibitors, HSF-1 inhibitors and anti-cancer naphthoquinones and naphthylisoquinoline for the treatment of multiple myeloma (Applicants Bringmann, Gerhard ;  Holzgrabe, Ulrike ;  Sotriffer, Christoph )
• In vivo models for the functional analysis of YB-1 in multiple myeloma (Applicants Bargou, Ralf C. ;  Bommert, Kurt )
• Regulation, integration and impact of NFkB-signaling within the oncogenic signaling network in multiple myeloma (Applicants Siegmund, Daniela ;  Stühmer, Thorsten ;  Wajant, Harald Günther )
• Role of CD28-mediated signaling in multiple myeloma (Applicant Berberich, Ingolf )
• Systematic shRNA screens for the analysis of critical signaling pathways in KRAS-mutant multiple myeloma (Applicant Eilers, Martin )
• Systemic shRNA screens and high throughout sequencing to investigate pathway dependence in multiple myeloma (Applicants Eilers, Martin ;  Rosenwald, Andreas )
• The heat shock protein/signaling interface as a therapeutic target in multiple myeloma and in Graft-versus-Host-Disease (Applicants Chatterjee, Manik ;  Einsele, Hermann )

• Spokesperson: Professor Dr. Hermann Einsele
• Leader: Professor Dr. Ralf C. Bargou