Clinical Cooperation Unit Molecular Hematology/Oncology – Research Projects

As a clinical cooperation unit, we are dedicated to knowledge transfer from basic research to clinical application. Hence, our research activities include basic, translational and clinical research projects.

CIN (Chromosomal Instability)

Our basic research is focused on mechanisms of chromosomal instability, an important hallmark of cancer cells, with special attention to the regulation of mitosis and its disturbance in the context of tumorigenesis. Since centrosomal aberrations have been shown to lead to mitotic aberrations and chromosomal instability, a long-standing focus of our group is centrosome biology and its interconnection to malignant transformation and metastasis. Ongoing projects include the generation and characterization of transgenic mice which overexpress the centriole replication protein STIL, in order to determine whether supernumerary centrosomes do cause chromosomal instability and subsequent tumor formation in vivo.

To map the landscape of centrosome aberrations in primary tumor tissues at high resolution, we use correlative light and electron microscopy (CLEM), focused ion beam scanning electron microscopy (FIB/SEM) and EM tomography with subsequent 3D reconstruction and quantitative analysis.

CUP (Carcinoma of Unknown Primary)

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Clinical Research

To determine efficacy and safety of targeted or immunotherapy guided by genomic profiling, we have initiated an international, randomized, multi-center phase II study (CUPISCO). This trial is performed in 188 centers from 34 countries and will include total of 790 patients with newly diagnosed CUP syndrome. The experimental arm of the trial includes 8 targeted and 2 immunotherapy strata.

To determine the impact of immune checkpoint inhibition in patients with platinum-resistant/refractory CUP syndrome, we have initiated a national, multicenter phase II study (CheCUP). This trial is performed at 10 German centers and will include a total of 194 patients who receive dual checkpoint inhibitor therapy with nivolumab and ipilimumab. Tumor mutational burden (TMB) will be analyzed as potential predictive marker for response to immune checkpoint inhibitor treatment.

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Translational Research

Current translational research projects employ genome-wide methylation profiling of large cohorts of primary CUP tumor samples for tissue-of-origin identification and analysis of DNA copy number variations, as chromosomal instability has been suggested to be a driving force of the metastatic process in CUP syndrome. Along the same lines, we analyze the role of micronucleus-driven cGAS-STING signaling in metastasis formation.

Using patient-derived organoids, we perform in vitro drug screening, primary tumor identification and functional in-depth characterization of the role of chromosomal instability for metastasis formation and clonal evolution/heterogeneity with CUP syndrome serving as a paradigm disorder for metastatic malignancies.

Translational Myeloma Research Group

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Current treatment strategies against multiple myeloma are based on a combination of proteasome inhibitors, immune modulatory drugs, and monoclonal antibodies, as well as chemotherapy with autologous stem cell transplantation. Despite improved survival rates, long term remission or even cure is still rarely achieved. Personalizing tumor specific therapy is currently explored to improve the outcome of specific patient groups by correlating genomic, proteomic and clinical data of refractory myeloma patients. In order to understand mechanisms underlying drug resistance in multiple myeloma, we compare the evolution of the clonal structure of tumor cells along treatment in clinical trials and routine care with the aim to discover novel therapeutic targets in refractory disease. By combining NGS-based readouts (WGS, RNAseq, scRNAseq, scATACseq, CiteSeq) with proteome-based technologies we comprehensively map cellular signaling profiles in order to identify biomarkers as well as novel therapeutic targets. We further focus on tumor heterogeneity within individual multiple myeloma patients to understand the full spectrum of disease biology and specifically the role of residual tumor cells in clinical remission. Overall, our goal is to understand the complex processes underlying the heterogeneity of this disease. We aim to discover molecular mechanisms that lead to drug resistance, impairment of the immune microenvironment, and result in novel therapeutic targets. Due to our strong clinical affiliation with the University Hospital, we successfully translate our discoveries in clinical application.

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