A5018550667- Ubiquitin and proteasome pathways
- Peptidase Inhibition and Analysis
- AI in cancer detection
- Cell Image Analysis Techniques
- Radiomics and Machine Learning in Medical Imaging
- Cancer Immunotherapy and Biomarkers
- Immune Cell Function and Interaction
- RNA modifications and cancer
- CAR-T cell therapy research
- Multiple Myeloma Research and Treatments
- Protein Degradation and Inhibitors
- Lung Cancer Treatments and Mutations
- Lung Cancer Research Studies
- Histone Deacetylase Inhibitors Research
- Immune cells in cancer
- Acute Myeloid Leukemia Research
- Microfluidic and Bio-sensing Technologies
- Cytokine Signaling Pathways and Interactions
- Phagocytosis and Immune Regulation
- Single-cell and spatial transcriptomics
- Immunotherapy and Immune Responses
- Molecular Biology Techniques and Applications
- Epigenetics and DNA Methylation
- Monoclonal and Polyclonal Antibodies Research
- Lymphoma Diagnosis and Treatment
AstraZeneca (Germany)
2022-2025
AstraZeneca (Brazil)
2024
Humboldt-Universität zu Berlin
2021-2024
Charité - Universitätsmedizin Berlin
2019-2024
Freie Universität Berlin
2021-2024
Bayer (Germany)
2024
Max Delbrück Center
2022-2024
German Cancer Society
2024
Deutschen Konsortium für Translationale Krebsforschung
2024
AstraZeneca (United States)
2023-2024
Pancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognosis with an overall 5-year survival rate of 9%. Conventional combination chemotherapies are clear advance in the treatment PDAC; however, subtypes disease exist, which exhibit extensive resistance to such therapies. Genomic MYC amplifications represent distinct subset PDAC aggressive tumour biology. It is that hyperactivation generates dependencies can be exploited therapeutically. The aim study was find and target...
Activated SUMOylation is a hallmark of cancer. Starting from targeted screening for SUMO-regulated immune evasion mechanisms, we identified an evolutionarily conserved function activated SUMOylation, which attenuated the immunogenicity tumor cells. allowed cancer cells to evade CD8+ T cell-mediated immunosurveillance by suppressing MHC class I (MHC-I) antigen-processing and presentation machinery (APM). Loss MHC-I APM frequent cause resistance immunotherapies, pharmacological inhibition...
Abstract Background We explored potential predictive biomarkers of immunotherapy response in patients with extensive-stage small-cell lung cancer (ES-SCLC) treated durvalumab (D) + tremelimumab (T) etoposide-platinum (EP), D EP, or EP the randomized phase 3 CASPIAN trial. Methods 805 treatment-naïve ES-SCLC were (1:1:1) to receive T EP. The primary endpoint was overall survival (OS). Patients required provide an archived tumor tissue block (or ≥ 15 newly cut unstained slides) at screening,...
Abstract Many targeted cancer therapies rely on biomarkers assessed by scoring of immunohistochemically (IHC)-stained tissue, which is subjective, semiquantitative, and does not account for expression heterogeneity. We describe an image analysis-based method quantitative continuous (QCS) digital whole-slide images acquired from baseline human epidermal growth factor receptor 2 (HER2) IHC-stained breast tissue. Candidate signatures patient stratification using QCS HER2 subcellular...
Signaling by the ubiquitin-related SUMO pathway relies on coordinated conjugation and deconjugation events. SUMO-specific deconjugating enzymes counterbalance SUMOylation, but comprehensive insight into their substrate specificity regulation is missing. By characterizing SENP6, we define an N-terminal multi-SIM domain as a critical determinant in targeting SENP6 to chains. Proteomic profiling reveals network of functions at crossroads chromatin organization DNA damage response (DDR). acts...
Acute myeloid leukemia originates from leukemia-initiating cells that reside in the protective bone marrow niche. CXCR4/CXCL12 interaction is crucially involved recruitment and retention of within this Various drugs targeting pathway have entered clinical trials. To evaluate CXCR4 imaging acute leukemia, we first tested expression patient-derived primary blasts. Flow cytometry revealed high blast counts patients with correlate expression. The wide range surface was reflected cell lines...
Abstract B-cell lymphoma (BCL) is the most common hematologic malignancy. While sequencing studies gave insights into BCL genetics, identification of non-mutated cancer genes remains challenging. Here, we describe PiggyBac transposon tools and mouse models for recessive screening show their application to study clonal lymphomagenesis. In a genome-wide screen, discover related diverse molecular processes, including signaling, transcriptional regulation, chromatin or RNA metabolism....
Evasion from drug-induced apoptosis is a crucial mechanism of cancer treatment resistance. The proapoptotic protein NOXA marks an aggressive pancreatic ductal adenocarcinoma (PDAC) subtype. To identify drugs that unleash the death-inducing potential NOXA, we performed unbiased drug screening experiment. In NOXA-deficient isogenic cellular models, identified inhibitor transcription factor heterodimer CBFβ/RUNX1. By genetic gain and loss function experiments, validated mode action depends on...
Abstract SUMOylation is a post-translational modification of proteins that regulates these proteins’ localization, turnover or function. Aberrant frequently found in cancers but its origin remains elusive. Using genome-wide transposon mutagenesis screen MYC-driven B-cell lymphoma model, we here identify the SUMO isopeptidase (or deconjugase) SENP6 as tumor suppressor links unrestricted to development and progression. Notably, recurrently deleted human lymphomas deficiency results...
Proteasome inhibition is a highly effective treatment for multiple myeloma (MM). However, virtually all patients develop proteasome inhibitor resistance, which associated with poor prognosis. Hyperactive small ubiquitin-like modifier (SUMO) signaling involved in both cancer pathogenesis and progression. A state of increased SUMOylation has been aggressive biology. We found that relapsed/refractory MM characterized by SUMO-high state, high expression the SUMO E1-activating enzyme (SAE1/UBA2)...
Aberrant activity of the glycoprotein 130 130/JAK/STAT3 (gp130/JAK/STAT3) signaling axis is a recurrent event in inflammation and cancer. In particular, it associated with wide range hematological malignancies, including multiple myeloma leukemia. Novel targeted therapies have only been successful for some subtypes these underlining need developing robust mouse models to better dissect role this pathway specific tumorigenic processes. Here, we investigated selective gp130/JAK/STAT3...
The IL-6–gp130–STAT3 signaling axis is a major regulator of inflammation. Activating mutations in the gene encoding gp130 and germline gain-of-function STAT3 (STAT3 GOF ) are associated with multi-organ autoimmunity, severe morbidity, adverse prognosis. To dissect crucial cellular subsets disease biology involved activated signaling, gp130-JAK-STAT3 was constitutively using transgene, L-gp130 , specifically targeted to T cells. cells vivo resulted fatal, early onset, autoimmunity mice that...
Abstract Aberrant CXCR4 activity has been implicated in lymphoma pathogenesis, disease progression, and resistance to therapies. Using a mouse model with gain-of-function mutation ( C1013G ) that hyperactivates signaling, we identified as crucial activator of multiple key oncogenic pathways. hyperactivation resulted an expansion transitional B1 lymphocytes, which represent the precursors chronic lymphocytic leukemia (CLL). Indeed, led significant acceleration onset more aggressive phenotype...
Abstract Background: Anti-PD-L1 therapy has demonstrated clinical activity in patients with metastatic non-small cell lung cancer (mNSCLC). However, only subgroups of respond and their identification via PD-L1 as a biomarker remains imperfect. expression is commonly assessed by pathologist tumor (TC) scoring immunohistochemically (IHC) stained tissue. We developed system for digitally IHC (PD-L1 QCS), which robust across studies [1]. Here, we present comparison QCS against manual (SP263...
Abstract Background: Volrustomig (MEDI5752) is designed to fully inhibit PD-1 while preferentially inhibiting CTLA-4 on activated PD-1+ T cells. In a FTiH trial, volrustomig demonstrated meaningful clinical activity in patients with solid tumors (including 1L RCC and NSCLC), acceptable safety profile, sustained receptor occupancy, cell proliferation at levels greater than seen clinically tolerable doses of inhibitors co-administration anti-PD(L)-1. We sought further characterize...
Transcriptional regulators play a major role in most biological processes. Alterations their activities are associated with variety of diseases and particular tumor development progression. Hence, it is important to assess the effects deregulated on pathological processes.Here, we present REGulator-Gene Association Enrichment (REGGAE), novel method for identification key transcriptional that have significant effect expression given set genes, e.g. genes differentially expressed between two...
Abstract. While the regulation of progesterone secretion from corpus luteum by LH has been convincingly demonstrated, secretory patterns in absence any pituitary inputs are yet unclear. Consequently, we investigated an vitro perifusion system to characterize spontaneous release isolated bovine luteum. Slices (120 mg) midluteal corpora lutea were placed chambers and continuously perifused Medium-199 for 160-320 min. Progesterone was determined radioimmunoassay effluent fractions collected at...
Biomarkers that predict response to lenalidomide maintenance therapy in patients with multiple myeloma (MM) have remained elusive. We shown immunomodulatory drugs (IMiDs) exert anti-MM activity via destabilization of MCT1 and CD147. In this study, cell samples 654 MM who received (n = 455), thalidomide 98), or bortezomib 101) were assessed by gene expression profiling RNA sequencing, followed correlation CD147 data for progression-free survival (PFS) overall (OS). Patients high levels showed...
Aberrant activity of the SUMOylation pathway has been associated with MYC overexpression and poor prognosis in aggressive B-cell lymphoma (BCL) other malignancies. Recently developed small-molecule inhibitors (SUMOi) target heterodimeric E1 SUMO activation complex (SAE1/UBA2). Here, we report that activated signaling is an actionable molecular vulnerability vitro a preclinical murine vivo model MYC-driven BCL. While SUMOi conferred direct effects on cells, inhibition also resulted...