Prof. Dr. Claudia Scholl
Applied Functional Genomics
The overarching goal of our research is to identify molecular abnormalities in human cancer cells that are important for the initiation and/or maintenance of the transformed phenotype, with particular focus on alterations that can be exploited to design better therapeutic strategies.
We are using proteomic and functional genomic tools to study signaling pathways that are essential for the transforming activity of mutant KRAS, the most frequently mutated oncogene in human cancers, with the aim to identify potentially druggable “Achilles’ heels” in KRAS-mutant cancer cells.
Much of the work in the laboratory focuses on the characterization of the mechanism(s) underlying the synthetic lethal relationship between transforming KRAS mutations and suppression of STK33, including the elucidation of the signaling pathways through which STK33 might function in mutant KRAS-dependent cells.
Furthermore, we are currently building a platform to systematically determine the essentiality of structural alterations identified in human cancer genomes and to identify patterns of non-oncogene addiction.
Within a long-standing collaboration with the group of Prof. Stefan Fröhling, we are working on the identification and characterization of vulnerabilities in acute myeloid leukemia (AML), the most common acute leukemia in adults.
Applied Stem Cell Biology
Prof. Dr. Hanno Glimm
Research projects of the Applied Stem Cell Biology Section (Head: Hanno Glimm) characterize the function and the genetic modification of stem cells and the role of their functional equivalents for the development and progression of cancer.
The group has extensive expertise in the isolation, genetic modification and functional evaluation of normal hematopoietic stem cells as well as solid tumor initiating cells. Comprehensive mechanistic analysis of clonal dominance and proprietary high-throughput genomics are used to study the cellular and molecular mechanisms of disease initiation, progression and metastasis formation of cancer initiating cells as well as equivalent mechanisms in leukemia, towards the identification of new therapeutic targets.
Discoveries on the mechanisms of tumor initiation, self-renewal, metastasis and heterogeneity of tumor-initiating cells and of the step-wise malignant transformation will be translated into clinical strategies.
Adaptive Immunity and Lymphoma
Dr. Dr. Sandrine Sander
Our research aims for a better understanding of physiological and pathological differentiation processes in the immune system, with a particular interest in B cells and their malignant transformation during the germinal center reaction. Using innovative in vivo models we characterize the regulating principles of immunity and tumorigenesis and thereby develop new therapeutic strategies for lymphoma patients.
Conditional mouse models are the focus of our research activities. In these animals genetic aberrations that have been identified in human lymphomas are introduced specifically in the presumed cell of tumor origin. Using this approach we are able to prove the oncogenicity of human mutations in an in vivo system. Based on high-throughput methods tumor-specific aberrations and their impact on immunological processes, such as the germinal center reaction, are characterized in the animals.
Using these models, we also elucidate signaling pathways that are vital for normal and malignant B-cells. In this context the B-cell receptor-mediated signaling cascade is of particular importance since it is active in many lymphomas and the focus of new drug therapies. With the aid of newly developed mouse strains, we will investigate B-cell receptor dependent signaling pathways and clarify their significance for lymphoma development and progression. Based on a better understanding of the molecular mechanisms of tumorigenesis, we want to develop improved strategies for the treatment of cancer patients.
Molecular and Gene Therapy
Dr. Manfred Schmidt
The main focus of the Molecular and Gene Therapy group is set on defining the efficiency and safety of gene transfer vector systems and their application in clinical gene therapy.
For nearly all successful gene therapy studies worldwide that have the aim of curing immunodeficiencies, the group surveyed the clonal composition of the hematopoietic system after transplantation. These studies also provided precious insight into the biology of stem cells, physiology of hematopoietic (and other tissue) regeneration and development of malignancies. Based on complex PCR technologies (i.e. LAM-PCR), next-generation sequencing and bioinformatic data management, the group implemented a highly valuable safety and insertional mutagenesis platform for more than 40 national and international collaborative projects that investigate molecular mechanisms underlying gene and molecular therapeutical studies.
Further research activities include cancer genomics (International Cancer Genome Consortium), innovative genome editing and targeting assays (i.e. ZFN, TALEN, CRISPR/Cas), molecular biology of wild-type HIV, immunogenetics (i.e. T cell receptor repertoire analyses and sequencing), DNA damage and repair, bioinformatics (i.e. graph theory, systems biology).
Figure: A largely random AAV integration profile after LPLD gene therapy
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Dr. Stefan Gröschel
Our scientific objectives are to understand pathways of gene regulation and to develop insights with innovate technologies to control gene expression in cancers driven by EVI1, most prominently acute myeloid leukemia. Together with collaboratives from our group and industry alliances we aim to translate these ideas as cancer therapeutic strategies.
Regulated expression of genes is orchestrated by surrounding control sequences, so-called „enhancers“. Enhancers can engage with target genes in different 3D nuclear chromatin interaction networks and function as cell type specific switches depending on tissue context, resulting in distinct gene expression programs that maintain cellular identity. This regulatory principle is exploited by oncogenes during tumorigenesis by 3D reorganization of enhancer-gene communications (enhancer hijacking). These physical interactions are either induced by gross chromosomal alterations (inversions, translocations, amplifications) or more subtle changes to the DNA code or even as aberrant dynamic chromatin changes without disruption of the linear DNA template.
Deregulation of the EVI1 oncogene is a key transforming event in the development of many malignancies and was initially discovered in high-risk leukemias, but remains largely unexplored in other entities, for example soft tissue sarcoma and other solid organ cancers. Both EVI1 function and the mechanism underlying its deregulation are poorly understood and the consequent lack of a targeted therapy against EVI1 creates a formidable clinical challenge. By applying functional genome diagnostics (next-generation sequencing-based, e.g. ChIP, targeted locus proteomics, 4C chromatin analysis) and genome editing (CRISPR technology) we aim to explore ways to reprogram the cancer cell's fundamental identity and revert the aggressive phenotype of these EVI1+ cancers. Toward these goals, we are also part of the ENHANCE consortium of the DKFZ, a highly interactive joint research collaboration of investigators from the DKFZ involved in basic and translational research with a focus on epigenetics.
Figure: ChIP-seq and 4C-seq (middle panel) in myeloid blast cells (left panel) nominates a candidate EVI1 superenhancer, that can be targeted by CRISPR/Cas9. Deletion of the superenhancer leads to monocytic differentiation of blast cells.
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Molecular Therapy in Haematology and Oncology
Prof. Dr. Thorsten Zenz
The main focus of our group is to 1) advance our understanding of molecular and genetic lesions in the pathogenesis of lymphoma subtypes and 2) use this understanding to exploit it therapeutically.
Over the last years, we have contributed to the understanding how genetic lesions contribute to lymphomagenesis. One particular focus of the group has been to define the role of the p53 pathway and particular mutant p53 in lymphoma. In addition to the assessment of molecular and clinical consequences of these genetic lesions, we focus on the identification of alternative drivers of disease traits.
To develop rational and biology-based ways for patient benefit from advances in molecular understanding and targeted drug treatment, we pursue an innovative strategy based on the comprehensive mapping and understanding of individual cancers’ vulnerability to compounds, pathway inhibitors and drugs as well as genome-wide silencing triggers (RNAi, CRISPR).
We systematically map pathway sensitivity (and resistance) of primary tumor cells ex vivo using diverse and relevant compound library across leukemia and lymphoma. By analysing response patterns of sensitivity and resistance we group tumors functionally, by response phenotype. In parallel, we directly associate and understand drug actions and their variability by investigating the underlying (causative) genetic or epigenetic changes, critical pathway activation, metabolic changes, the biology of the cell of origin and the microenvironment.
Following the identification of clinically actionable vulnerabilities on primary tumors, we will mechanistically validate these with in vitro (incl. RNAi) and in vivo models and develop rational starting points for clinical development. We classify disease based on pathway sensitivity and the systematic understanding of underlying molecular networks.
We combine local expertise and cooperation with strong national and international cooperation (DKTK, DCLLSG, ERIC, CCE) to develop competitive clinical and research platforms to specifically focus on lymphoproliferative disease (LPD).
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Molecular and Cellular Oncology
Prof. Dr. Stefan Fröhling
Research in the Section of Molecular and Cellular Oncology (Head: Stefan Fröhling) is centered around the identification of new cancer drug targets through a better understanding of the functional properties of selected hematologic and solid-organ malignancies, and to translate these insights into clinical application.
Current projects focus on genotype-specific vulnerabilities and patterns of protein kinase dependence in acute myeloid leukemia, and the delineation of essential signaling pathways in soft-tissue sarcoma and epithelial cancers driven by oncogenic KRAS mutations. The Section is also involved in the clinical implementation of prospective, cross-entity cancer genome sequencing within the NCT Precision Oncology Program, and aims to devise strategies for parallel functional annotation of newly discovered, potentially “actionable” genetic lesions.
Figure: Identification of Context-Dependent Therapeutic Targets in Acute Myeloid Leukemia, Soft-Tissue Sarcoma, and Epithelial Cancers
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Prof. Dr. Dr. Guy Ungerechts
Towards molecular cancer therapy, the Max Eder group develops novel oncolytic viruses based on measles virus (MV) vaccine. These vectors have been engineered to display ligands and single-chain antibodies for tumor-specific targeting on the cell entry level. Currently, the tumor-targeting strategy for MV is further developed by taking advantage of microRNA techniques ("Targeting 2.0").
MicroRNA-based regulation of oncolytic MV for tissue-specific replication is achievable by introducing synthetic microRNA target sequences into the viral genome.
Armed MV encoding suicide genes, including the herpes simplex virus thymidine kinase, the cytosine deaminase and the purine nucleoside phosphorylase from Escherichia coli, have been developed to support tumor lysis.
In the attempt to deliver oncolytic therapeutics effectively to the tumor site, shielded virus vectors displaying glycoproteins from other paramyxoviruses have been engineered that can evade pre-existing MV antibodies.
Next-generation measles viruses for immunovirotherapy approaches have been successfully tested in preclinical models and are currently in phase I clinical trial development. In a combined immunovirotherapy, MV is engineered for enhanced efficacy via modulation of the patients’ immune response in terms of augmented tumor vaccination effects. These novel cancer therapeutics allow for anti-tumor activity by overcoming immune tolerance against cancer cells via triggering pathways of T cell activation.
Altogether, several strategies have contributed to further optimize oncolytic MV vectors in terms of their safety and efficacy for translation toward clinical applications.
Figure: Three main strategies contribute to the optimization of oncolytic mealses virus vectors for translation toward clinical applications concerning safety and efficacy in cancer therapy: Arming and Targeting, Targeting 2.0 and Stealthing. Prospectively, a combined immunovirotherapy will be tested in a clinical phase I study.
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NCT has implemented the NCT Precision Oncology Program (NCT POP) as a center-wide master strategy that, together with NCT’s dedicated Clinical Cancer Programs, coordinates all translational activities and focuses resources towards individualized cancer medicine, including patient-oriented strategies in genomics, proteomics, immunology, radiooncology, prevention, and early clinical development. For this purpose, the center-wide NCT MASTER (Molecularly Aided Stratification for Tumor Eradication) umbrella protocol has been created to provide a comprehensive platform for individualized cancer medicine working towards a comprehensive, multidimensional characterization of all cancer patients seen at NCT/HUMS. DKFZ-HIPO, the DKFZ Sequencing Core Facility, and bioinformatics groups on campus and NCT POP provide platforms for the application of HT sequencing for molecular profiling of human cancers and streamline data acquisition and analysis.
Within more than 50 pilot projects, which have expanded rapidly towards prospective studies, these programs provide high-resolution genetic information on large patient cohorts that is managed in a central data repository, allowing for comprehensive cross-entity analyses. Important examples include systematic epigenetic profiling (C. Plass, F. Lyko), detailed quantitative immunomics (P. Beckhove, D. Jäger, M. von Knebel Doeberitz), and characterization of the tumor-initiating cell compartment in various cancers (H. Glimm, A. Trumpp). Additional layers of characterization focus on determining the functional properties of specific cancer genotypes – using both genetic (M. Boutros, H. Glimm, S. Fröhling, C. Scholl) and pharmacologic (T. Zenz, SMART Consortium) perturbations – and systematic proteomic studies of primary human cancer specimen.
The ultimate goal of this multidisciplinary center-wide effort in precision oncology is to provide a validated workflow for trials to infer rational recommendations for mechanism-based therapeutic interventions in advanced malignancies and improve patients care by integrating systematic molecular data.