Pathogenesis of ASXL1mutated AML; deciphering mechanisms for novel rational interventions

This project aims to deepen our molecular understanding of ASXL1-mutated (ASXL1mut) acute myeloid leukemia (AML). ASXL1mut frequently occur in myeloid malignancies and, especially in AML, are accompanied by an unfavorable prognosis. By combining Asxl1mut with a genetic system randomly causing mutations, leukemia occurs in mice. After sequencing, Asxl1mut AML are compared to large-scale human ASXL1mut AML datasets, enabling the pinpointing of novel crucial events in leukemogenesis. The most promising identified cancer genes are then (pre)clinically validated for their therapeutic use, e.g., through the development of biomarkers or individualized targeted (combination) therapies. 
 

Department of Hematology, Oncology and Cancer Immunology
Campus Benjamin Franklin 

Charité - Universitätsmedizin Berlin

Berlin, Germany

E-Mail: francis.baumgartner@charite.de

Unveiling interactions between senescent tumor cells and the host immune system - Implications for Senolytic Immunotherapy

Therapy-induced senescence (TIS) prevents tumor growth and improves treatment outcome in many preclinical cancer models. TIS also alters the tumor biology and environment, contributing to treatment resistance and tumor relapse. There is a close relationship between senescent tumors and the host immune system, but the molecular mechanism of their interaction remains unclear and contingent upon cancer type. Using spatial proteomic, biochemistry and molecular biology techniques, the aim of my project is to characterize the interactions between senescent tumor and the host immune system to identify new actionable moieties to improve the efficacy of senolytic immunotherapies in different cancers. 
 

Laboratory of Tumor heterogeneity and treatment resistance in pediatric cancer, Department of Pediatric Oncology/Hematology

Experimental and Clinical Research Center (ECRC) of the MDC and Charité-Universitätsmedizin Berlin, Germany

Berlin, Germany

E-Mail: bartolomeo.bosco@charite.de

Using DNA methylation profiling for differential diagnosis and for determining the origin of ovarian cancers

My research interests lie in classifying, solving differential diagnosis problems, and determining the origin of ovarian cancers. We are using DNA methylation data to develop machine learning algorithms for analyzing ovarian tumors. DNA methylation patterns are highly tissue specific, hence are an ideal method for performing differential diagnosis. Currently, we aim to develop a machine learning classifier that can differentiate subtypes of ovarian carcinomas. Additionally, we aim to use DNA methylation data to predict the outcome of and to subclassify ovarian carcinomas. We plan to expand our research to other female reproductive system tumors.
 

Institute of Pathology, Charité - Universitätsmedizin Berlin

Berlin, Germany

E-Mail: mihnea.dragomir@charite.de

The Role of Radiotherapy in the Treatment of Atypical Meningiomas – A Methylome- and Genome-based Analysis

The role of an adjuvant radiotherapy for grade 2 meningiomas remains unclear. The traditional approach of meningioma diagnosis using only light microscopy and immunohistochemistry to distinguish the current subclasses is prone to interobserver biases and limited regarding personalized treatment decision making. This knowledge gap is highlighted by contradictory findings in various studies. By implementing a DNA-methylation-based classifier and incorporating genetic risk factors to ensure accurate tumor subtype identification, the project aims to specifically assess the role of adjuvant radiotherapy in a homogenous meningioma cohort. 
 

Department of Radiation Oncology, Charité - Universitätsmedizin Berlin

Berlin, Germany

Email: felix.ehret@charite.de

Understanding and circumventing resistance to targeted immunotherapy in pediatric relapsed/refractory B-cell precursor acute lymphoblastic leukemia

Targeted immunotherapy, e.g. with the CD19-directed bispecific T-cell engager Blinatumomab or the CD22-directed toxin-conjugated monoclonal antibody Inotuzumab/Ozogamicin, has significantly improved the outcome of patients with pediatric r/r BCP-ALL. However, several resistance mechanisms have been observed. As a prerequisite for circumventing treatment failure, our research module aims at elucidating the underlying intrinsic or acquired resistance mechanisms. Furthermore, we investigate their relevance in clinical subgroups and try to identify predictors of response failure. We thereby hope to improve precision medicine concepts in upcoming clinical trials for pediatric r/r BCP-ALL. 
 

Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum
Klinik für Pädiatrie mit Schwerpunkt Onkologie, Hämatologie und Stammzelltransplantation

Berlin, Germany

E-Mail: jonas.grauhan@charite.de

Functional relevance of DNA circularization and its contribution to genetic heterogeneity and evolution in childhood solid tumours

My work aims to assess changes in extrachromosomal circular DNA (ecDNA) heterogeneity over time using various cell types and sequencing techniques. Insights from these data will help determine how circular DNA elements are selected for and expressed in the context of enhanced proliferation. Understanding the nature and clinical importance of ecDNA is currently limited by our ability to reconstruct entire circles and genomic fragments contained therein. Hence, my project involves adaption and integration of existing methods, as well as development of new algorithms to reliably quantify and reconstruct ecDNA elements from bulk and single-cell sequencing data at clinically relevant time points.

Functional genomics of paediatric cancers group, Experimental and Clinical Research Center (ECRC) of the Max Delbrück Center (MDC) and Charité Berlin

Postdoctoral Computational Biologist

Berlin, Germany

E-Mail: kerstin.haase@charite.de

Identification and validation of genetic and cellular biomarkers for patient stratification, prognosis and early detection of resistance mechanisms in the context of tumor therapy

My research interests lie in understanding and deciphering the molecular mechanisms underlying tumorigenesis and cause targeted and/or immune checkpoint inhibitor therapies to fail. Currently, we focus on biobanking for the purpose of comprehensive genomic tumor characterization and the implementation of liquid biopsy. Second, we study immune adverse events, especially in the skin, during immune checkpoint therapy to understand and compare the underlying molecular mechanism to inflammatory and autoimmune diseases of the skin. Third, we are interested in the different compartments of the immune system fighting cancer, particularly the role of the dendritic cells and the killing by granzymB.
 

Department Dermatology, Venereology and Allergology, Charité - Universitaetsmedizin Berlin

AG Molecular Immunology Charité
Head of Experimental Research

Berlin, Germany

E-Mail: franz.hilke@charite.de
 

Classical and Therapy-Associated Clonal Hematopoiesis (CH) in Patients With Chronic Lymphocytic Leukemia (CLL)

Clonal hematopoiesis (CH) refers to the presence of mutant blood cell clones, a condition that is prevalent among the elderly population. Its significance extends to various clinical conditions, notably cardiovascular and malignant diseases. My project aims to explore the clinical and mechanistic implications of CH in CLL patients. Besides classical CH genes, I focus on mutations associated with targeted therapies, deciphering the behavior of the hematopoietic system under novel kinds of selection pressure. In addition to sequencing techniques, I employ CRISPR/Cas9 to create mutant CH model systems.

Medizinische Klinik m.S. Hämatologie, Onkologie und Tumorimmunologie
Campus Virchow-Klinikum, Charité – Universitätsmedizin Berlin

Berlin, Germany

E-Mail: benjamin.locher@charite.de

Extrachromosomal MYCN amplification dynamics enable rapid adaptation to chemotherapy in neuroblastoma

Neuroblastoma commonly affects very young children. Despite their generally positive initial response to treatment, these tumors frequently recur with surprising resistance. This is especially puzzling since neuroblastomas typically show little genetic heterogeneity at diagnosis, pointing to unknown rapid adaptation mechanisms. By utilizing bulk and single-cell sequencing, as well as spatial proteomics analyses, we've found that extrachromosomal DNA (ecDNA)-driven genetic heterogeneity leads to variations in treatment response among cells containing MYCN amplification. This insight may explain why high-risk neuroblastomas can rapidly recur after initial treatment success.

Laboratory of Tumor heterogeneity and treatment resistance in pediatric cancer, Department of Pediatric Oncology/Hematology at Charité-Universitätsmedizin Berlin 

Experimental and Clinical Research Center (ECRC) of the MDC and Charité-Universitätsmedizin Berlin

Berlin, Germany

E-Mail: giulia.montuori@charite.de

 

Protein ubiquitination is a post-translational modification that leads to proteasomal degradation or altered function of a protein. My project aims to investigate the oncogenic role of deubuquitinating enzymes (DUBs) and their exploitation as drug targets in Acute Myeloid Leukemia (AML). Our preliminary CRISPR screenings for DUB inactivation identified USP7 to be essential for several AML cell lines. A combinatorial approach encompassing proteomic, biochemistry and molecular biology analyses will aim to identify novel the substrates of USP7 which are critical for AML. The results of this project will help to further understand the role of the ubiquitin-proteasome system in the pathogenesis of AML and to identify new therapeutic approaches.
 

Department of Hematology and Oncology

Charité – Universitätsmedizin Berlin

Berlin

E-Mail: arunima.murgai@charite.de

Genetic Characterization of Primary Mediastinal B cell Lymphoma

Unravelling genetic aberrations underlying PMBL lymphomagenesis has the potential to identify new targets for tailored therapy approaches. A thorough description of the mutational spectrum in PMBL and the identification of key oncogenic drivers will thus facilitate rational therapeutic approaches. Until now, we have collected the world’s largest PMBL cohort (n>400) through national and international collaborations comprising clinically well annotated patients. Using a combination of whole-exome, targeted deep resequencing and gene expression analysis, we aim to identify key oncogenic drivers and deregulated signaling pathways in PMBL. Based on the previous molecular analyses, functional consequences of candidate driver mutations will be analyzed in PMBL cell lines using the CRISPR/Cas technology.

Department for Hematology, Oncology and Tumor Immunology

German Cancer Consortium (DKTK), partner site Berlin

Berlin, Germany

E-Mail: daniel.noerenberg@charite.de

Exploring Paths of Tumorigenesis through the Characterization of the Human Somatic Mutational Landscape

Wat can we learn about disease from the healthy? To answer this question, in my current research project I focus on the molecular analysis of normal and diseased human tissues. Specifically, we analyze DNA-sequencing data from normal, precancerous, and cancerous tissues to analyze and compare mutational processes in the different stages of tumorigenesis. With this approach we aim to characterize different paths of tumorigenesis and identify yet unknown molecular tissues of origin of different cancer types.

Berlin Institute of Health, Department for Functional Diagnostics

Berlin, Germany

E-Mail: leonie.stockschlaeder@charite.de

Image-derived biomarkers from FDG-PET/CT for staging and prognosis in non-small cell lung cancer

The research aims at improving non-invasive pretherapeutic staging using FDG-PET/CT in patients with non-small cell lung cancer (NSCLC) using image-derived biomarkers (radiomics) and machine learning-based classifiers. A special focus is to improve thoracic lymph node staging. Furthermore, biomarkers are used to develop more differentiated prognostic models to predict patient survival after curatively intended treatment.

Department of Nuclear Medicine, Charité – Universitätsmedizin Berlin

Berlin, Germany

E-Mail: julian.rogasch@charite.de

Breaking Radioresistance of Soft Tissue Sarcomas by New Combination Therapies: Development of a Preclinical Pipeline

Despite their radioresistance and heterogeneity of over 70 subtypes, all soft tissue sarcomas (STS) are treated with the same perioperative radiotherapy regimen. Preclinical and clinical data on effective combination therapies of radiation and targeted compounds is scarce. This proof-of-concept study uses preclinical 3D models of STS to test two hypotheses: 1) Differences in radioresistance among STS subtypes can be reproducibly shown in 3D STS models; 2) New combination therapies of radiation + targeted compounds can overcome radioresistance in STS and be demonstrated in 3D STS models. The study lays the foundation for a preclinical drug and radiation screening platform for STS.
 

Department of Radiation Oncology

Charité – Universitätsmedizin Berlin

Berlin, Germany

Email: siyer.roohani@charite.de    

Link institutional website
Link Sarkom-Zentrum Charité website

Unraveling interplay between MYCN and cellular components in the immunosuppressive high-risk neuroblastoma microenvironment to enhance immunotherapy success

Half of high-risk neuroblastomas harbor amplifications of the MYCN oncogene, a key player in progression and metastasis and correlating with poor prognosis in pediatric patients. Chimeric antigen receptor (CAR) T cells offer a new approach against high-risk neuroblastoma. However, tumorassociated macrophages and cancer-associated fibroblasts, contribute with intertwined function to the immunosuppressive microenvironment, thus impeding CAR T cell efficacy. My research aims to uncover how oncogenic MYCN levels influence the presence, behavior, and function of macrophages and fibroblasts in the neuroblastoma microenvironment and how these components in turn hinder CAR T cell success.

Department of Pediatric Oncology and Hematology, University Hospital: Charité – Universitätsmedizin Berlin

Berlin, Germany

E-Mail: Karin.toews@charite.de

Characterizing the role of MACC1, a causal driver of cancer metastasis, in immune evasion

Metastasis accounts for >90% of cancer deaths. To improve patient outcomes, identifying (targetable) causal drivers of metastasis is essential. MACC1 acts as such a driver in more than 20 cancer entities. One key prerequisite for metastasis is the evasion of immune responses. Whilst MACC1 is central for many hallmarks of cancer, its effect on immunological processes remains poorly understood. Using spatial proteomics, high-throughput data sets and animal models, we aim to characterize the role of MACC1 in caner immune evasion. Characterizing metastatic potential and anti-tumor immunity will also help to improve the understanding of intervention strategies, specifically immunotherapies.

Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin
and Max-Delbrück Centrum for Molecular Medicine

Berlin, Germany

E-Mail: Sebastian.Torke@charite.de

Characterization of the tumor microenvironment, cellular composition and molecular changes in CNS metastases and primary brain tumors of therapy naive and pre-treated patients

The primary objective of our study is to characterize the tumor immune microenvironment (TIME), cellular composition, and molecular changes in brain metastases (BrM). The research aims to understand the interactions between tumor cells and their surrounding environment, especially in patients who have undergone different treatments. The study hypothesizes that the composition of the tumor microenvironment can be altered by prior treatments but on the other hand can also assist predict response to future treatments such immunotherapy. Using scalable and spatial techniques like multiplex immunohistochemistry, MALDI imaging as well as gene expression analyzes the study will analyze tissue samples to identify therapy-associated changes. 
Similarly, the project will employ an established pre-clinical ex vivo model using patient-derived explant cultures, which will facilitate experimental studies to define the functions of individual components of the tumor microenvironment. The ultimate goal is to identify potential resistance mechanisms to treatments and provide insights for future therapeutic strategies.

Department of Neurosurgery

German Cancer Consortium (DKTK), partner site Berlin
Campus Mitte Clinic, Charité Universitätsmedizin Berlin

Berlin, Germany

E-Mail: david.wasilewski@charite.de


 

SIGN-OC (SIGNature for neoadjuvant chemotherapy in Ovarian Cancer)

The gold standard of care for ovarian cancer consists of chemotherapy and debulking surgery but the debate on optimal treatment sequence is still ongoing. In the phase III AGO-OVAR TRUST trial,746 patients were randomized into two treatment arms, comparing neoadjuvant chemotherapy followed by surgery vs. upfront surgery. Our goal within the SIGN-OC JF program is to analyze clinical samples obtained within the TRUST trial to study mutational signatures and predictive biomarkers of chemotherapy response with a custom designed panel of 232 genes, including frequent alterations in ovarian cancer, with emphasis on HRR- and PI3K/AKT/mTOR pathway associated genes.

Charité - Universitätsmedizin Berlin

Medizinische Klinik m.S. Hämatologie, Onkologie und Tumorimmunologie CCM

Berlin, Germany

E-Mail: soo-ann.yap@charite.de

TCR based immunotherapy targeting senescence associated antigens in KRAS inhibitor resistant pancreatic cancer

This project aims to develop T cell receptor (TCR) based immunotherapies targeting senescence associated antigens in KRAS inhibitor resistant pancreatic cancer. Tumor cells that survive targeted therapy often enter a senescence like, therapy resistant state that promotes relapse. By identifying and targeting antigens specifically presented by these senescent cells, the project seeks to enable selective immune elimination of resistant tumor cells and improve long term treatment outcomes.

Research Group Metabolic Networks in Tumor Immunity

DKTK Berlin Site – German Consortium for Translational Cancer Research

Department of Hematology and Oncology

Berlin, Germany

E-Mail: nicolas.arnow@charite.de

 

Development of new multi-omics method “OmniOmix” to harness existing clinical archives for a better understanding of cancer development

The most effective strategies against cancer are prevention or early detection, both of which rely on identifying key molecular changes driving malignant transformation. A major challenge is our limited knowledge of the origin and earliest steps in the progression of many cancers. My goal is to establish a new technique that enables the use of archived formaldehyde-fixed paraffin-embedded (FFPE) samples to identify critical molecular changes. By allowing the comprehensive multi-omics profiling of small FFPE-derived cell clones the new method “OmniOmix” will facilitate the discovery of biomarkers for early detection.

Berlin Institute of Health

Center of Genomic Medicine

Berlin, Germany

E-Mail: francesca.tiso@bih-charite.de

 

Unraveling Mechanisms of Immune Escape in Melanoma Brain Metastases

Resistance to immune checkpoint inhibition in melanoma brain metastases remains a critical barrier to durable disease control. This project aims to dissect mechanisms of immune evasion within the neurocranial microenvironment using spatial transcriptomics of therapy-naïve and resistant tumors. Candidate resistance genes will be functionally interrogated by CRISPR/Cas9 in patient-derived models and profiled by RNA sequencing. Integrating experimental data with clinical outcomes will identify mechanisms of resistance and potential therapeutic targets.
 

Department of Hematology, Oncology and Cancer Immunology CVK

Charité - Universitätsmedizin Berlin

Berlin, Germany

E-Mail: elisa.schumann@charite.de
 

Deciphering the Molecular Landscape of Myeloid Malignancies 

Myeloid neoplasms such as MDS and MPN carry a risk of transformation to acute myeloid leukaemia (AML), with aberrations of chromosome 7 marking a group at particularly high risk. This project maps the mutational landscape of a large, well-annotated cohort of patients with chromosome 7 aberrant myeloid neoplasms to define molecular predictors of progression to AML. These predictors could enable risk-stratified monitoring, while also exploring the role of previously underappreciated mutations, with the long-term goal of translating this genomic complexity into personalized therapies.
 

Medizinische Klinik m.S. Hämatologie, Onkologie und Tumorimmunologie, Campus Virchow-Klinikum
 
Charité – Universitätsmedizin Berlin

Berlin, Germany

E-Mail: adriane.halik@charite.de