A5009251187- Histone Deacetylase Inhibitors Research
- Pancreatic and Hepatic Oncology Research
- Epigenetics and DNA Methylation
- Ubiquitin and proteasome pathways
- Advanced Breast Cancer Therapies
- Peptidase Inhibition and Analysis
- Protein Degradation and Inhibitors
- Cell death mechanisms and regulation
- Cancer Genomics and Diagnostics
- Phagocytosis and Immune Regulation
- Bladder and Urothelial Cancer Treatments
- Immune Cell Function and Interaction
- Cancer-related Molecular Pathways
- Multiple Myeloma Research and Treatments
- Computational Drug Discovery Methods
- RNA modifications and cancer
- Renal cell carcinoma treatment
- Protein Structure and Dynamics
- Cancer Cells and Metastasis
- Urinary and Genital Oncology Studies
- PARP inhibition in cancer therapy
- Autophagy in Disease and Therapy
- Metabolism, Diabetes, and Cancer
- PI3K/AKT/mTOR signaling in cancer
- Lung Cancer Treatments and Mutations
Charité - Universitätsmedizin Berlin
2020-2024
Humboldt-Universität zu Berlin
2021-2024
Deutschen Konsortium für Translationale Krebsforschung
2021-2024
Freie Universität Berlin
2021-2024
Max Delbrück Center
2022-2024
Technical University of Munich
2009-2024
Klinikum rechts der Isar
2009-2024
University of Göttingen
2023-2024
Universitätsmedizin Göttingen
2023-2024
German Cancer Research Center
2021-2024
Bioactive small molecules, such as drugs or metabolites, bind to proteins other macro-molecular targets modulate their activity, which in turn results the observed phenotypic effects. For this reason, mapping of bioactive molecules is a key step toward unraveling molecular mechanisms underlying bioactivity and predicting potential side effects cross-reactivity. Recently, large datasets protein–small molecule interactions have become available, providing unique source information for...
The SwissBioisostere database (http://www.swissbioisostere.ch) contains information on molecular replacements and their performance in biochemical assays. It is meant to provide researchers drug discovery projects with ideas for bioisosteric modifications of current lead molecule, as well give interested scientists access the details particular replacements. As August 2012, 21,293,355 datapoints corresponding 5,586,462 unique that have been measured 35,039 assays against 1948 targets...
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 Cancer cells must develop strategies to adapt the dynamically changing stresses caused by intrinsic or extrinsic processes, therapeutic agents. Metabolic adaptability is crucial mitigate such challenges. Considering metabolism as a central node of adaptability, it focused on an energy sensor, AMP‐activated protein kinase (AMPK). In subtype pancreatic ductal adenocarcinoma (PDAC) elevated AMPK expression and phosphorylation identified. Using drug repurposing that combined screening...
The c-MYC (MYC afterward) oncogene is well known for driving numerous oncogenic programs. However, MYC can also induce apoptosis and this function of warrants further clarification. We report here that a clinically relevant proteasome inhibitor significantly increases protein levels endogenous necessary the induction apoptosis. This kind MYC-induced cell death mediated by enhanced expression pro-apoptotic BCL2 family members NOXA BIM. Quantitative promoter-scanning chromatin...
We set out to determine whether clinically tested epigenetic drugs against class I histone deacetylases (HDACs) affect hallmarks of the metastatic process.We treated permanent and primary renal, lung, breast cancer cells with deacetylase inhibitors (HDACi) entinostat (MS-275) valproic acid (VPA), replicative stress inducer hydroxyurea (HU), DNA-damaging agent cis-platinum (L-OHP), cytokine transforming growth factor-β (TGFβ). used proteomics, quantitative PCR, immunoblot, single cell DNA...
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...
Phosphatidylinositol 3-kinase (PI3K) signaling controls survival and proliferation of cancer cells is activated in around 60% pancreatic ductal adenocarcinomas (PDACs). Although not entirely clarified, PI3K linked to cell cycle progression PDAC cells. In this study we demonstrate that transcription the E2F1 gene show essential for S-phase On molecular level, c-myc protein abundance a glycogen synthase kinase-3 (GSK3)-dependent fashion. binds E-box binding under control PI3K-signaling...
Histone deacetylases (HDACs) control fundamental physiological processes such as proliferation and differentiation. HDAC inhibitors (HDACi) induce cell cycle arrest apoptosis of tumor cells. Therefore, they represent promising cancer therapeutics that appear particularly useful in combination therapies. Although HDACi are tested current clinical trials, the molecular mechanisms modulating cellular responses toward incompletely understood. To gain insight into pathways limit efficacy gastric...
Although the mechanistic target of rapamycin (MTOR) kinase, included in mTORC1 and mTORC2 signalling hubs, has been demonstrated to be active a significant fraction patients with pancreatic ductal adenocarcinoma (PDAC), value kinase as therapeutic needs further clarification. We used Mtor floxed mice analyse function context pancreas at genetic level. Using dual-recombinase system, which is based on flippase-FRT (Flp-FRT) Cre-loxP recombination technologies, we generated novel cellular...
One of the major challenges in using pancreatic cancer patient–derived organoids (PDOs) precision oncology is time from biopsy to functional characterization. This particularly true for endoscopic ultrasound-guided fine-needle aspiration biopsies, typically resulting specimens with limited tumor cell yield. Here, we tested conditioned media individual PDOs cell-free DNA detect driver mutations already early on during expansion process accelerate genetic characterization as well subsequent...
The mortality of patients with pancreatic ductal adenocarcinoma (PDAC) is strongly associated metastasis, a multistep process that incompletely understood in this disease. Although genetic drivers PDAC metastasis have not been defined, transcriptional and epigenetic rewiring can contribute to the metastatic process. eraser histone deacetylase 2 (HDAC2) has connected less differentiated PDAC, but function HDAC2 comprehensively evaluated. Using genetically defined models, we show cellular...
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...
Systemic therapies for pancreatic ductal adenocarcinoma (PDAC) remain unsatisfactory. Clinical prognosis is particularly poor tumor subtypes with activating aberrations in the MYC pathway, creating an urgent need novel therapeutic targets. To unbiasedly find MYC-associated epigenetic dependencies, we conducted a drug screen cancer cell lines. Here, found that protein arginine N-methyltransferase 5 (PRMT5) inhibitors triggered dependency. In human and murine PDACs, robust connection of PRMT5...
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)...