A5066574696- Protein Degradation and Inhibitors
- Glioma Diagnosis and Treatment
- Histone Deacetylase Inhibitors Research
- Ubiquitin and proteasome pathways
- Epigenetics and DNA Methylation
- Ocular Oncology and Treatments
- PARP inhibition in cancer therapy
- Neuroblastoma Research and Treatments
- Cytokine Signaling Pathways and Interactions
- Melanoma and MAPK Pathways
- Multiple Myeloma Research and Treatments
- Cancer, Hypoxia, and Metabolism
- interferon and immune responses
- Laser Applications in Dentistry and Medicine
- DNA Repair Mechanisms
- Peptidase Inhibition and Analysis
St. Jude Children's Research Hospital
2023-2025
Hopp Children's Cancer Center Heidelberg
2017-2024
German Cancer Research Center
2017-2024
Heidelberg University
2017-2024
University Hospital Heidelberg
2023-2024
National Center for Tumor Diseases
2018-2024
Deutschen Konsortium für Translationale Krebsforschung
2017-2018
Epigenomics (Germany)
2017
Abstract Background Pilocytic astrocytoma (PA) is the most common pediatric brain tumor and a mitogen-activated protein kinase (MAPK)-driven disease. Oncogenic MAPK-signaling drives majority of cells into oncogene-induced senescence (OIS). While OIS induces resistance to antiproliferative therapies, it represents potential vulnerability exploitable by senolytic agents. Methods We established new patient-derived PA cell lines that preserve molecular features primary tumors can be studied in...
The sensitivity of myelocytomatosis oncogene (MYC) amplified medulloblastoma to class I histone deacetylase (HDAC) inhibition has been shown previously; however, understanding the underlying molecular mechanism is crucial for selection effective HDAC inhibitors clinical use. aim this study was investigate direct interaction MYC and HDAC2, impact on function.Co-immunoprecipitation mass spectrometry were used determine co-localization HDAC2. Chromatin immunoprecipitation (ChIP) sequencing gene...
Abstract Introduction Patients with pediatric low-grade gliomas (pLGGs), the most common primary brain tumors in children, can often benefit from MAPK inhibitor (MAPKi) treatment. However, rapid tumor regrowth, also referred to as rebound growth, may occur once treatment is stopped, constituting a significant clinical challenge. Methods Four patient-derived glioma models were investigated model growth vitro based on viable cell counts response MAPKi and withdrawal. A multi-omics dataset (RNA...
PROTACs usually occupy physicochemical space outside the one defined by classical drug-like molecules, which often presents considerable challenges in their optimization and development for oral administration. We have previously reported phenyl glutarimide (PG)-based BET PROTAC SJ995973, with improved overall vitro degradation antiproliferative activities compared to its direct thalidomide-based analogue dBET1, but similarly poor vivo pharmacokinetic profile. To further demonstrate PG...
Abstract Aurora A kinase (AURKA) is an oncogene frequently overexpressed in adult solid tumors, hematologic malignancies, and pediatric cancers. AURKA plays important role mitosis, cancer cells sensitive to loss of include lines derived from MYCN amplified tumors such as neuroblastoma, well those with RB1 neuroendocrine small cell cancers CDK4/6-resistant breast (Mou, et al., 2021). Several inhibitors are effective preclinical tumor models, but this activity has failed translate into...
Abstract Purpose We and others have demonstrated that MYC -amplified medulloblastoma (MB) cells are susceptible to class I histone deacetylase inhibitor (HDACi) treatment. However, single drug treatment with HDACi has shown limited clinical efficacy. hypothesized addition of a second compound acting synergistically may enhance Methods used gene expression dataset identify PLK1 as target in MB validated the relevance MB. measured cell metabolic activity, viability, cycle progression after...
MYC-driven Group 3 medulloblastoma (MB) (subtype II) is a highly aggressive childhood brain tumor. Sensitivity of MB to class I histone deacetylase inhibitors (HDACi) has been previously demonstrated in vitro and vivo. In this study we characterize the transcriptional effects HDACi explore beneficial drug combinations.MYC-amplified cells (HD-MB03) were treated with entinostat. Changes gene expression profile quantified on microarray. Bioinformatic assessment led identification pathways...
Abstract MYC family proteins are primary drivers of oncogenic processes in a variety cancer histologies. N-myc overexpression and amplification induce aggressive pediatric cancers, the most common which solid extracranial tumors children (neuroblastoma, NB) malignant CNS (medulloblastoma, MB). Due to addiction observed these tumor types, is considered an attractive therapeutic target. However, direct small molecule targeting remains technically challenging. Alternative approaches target this...
Abstract Patients with pediatric low-grade gliomas (pLGG), the most common primary brain tumor in children, can often benefit from MAPK inhibitor (MAPKi) treatment. However, rapid regrowth, also referred to as rebound growth, may occur once treatment is stopped, constituting a significant clinical challenge. Four patient-derived pLGG models were investigated model growth vitro based on viable cell counts response MAPKi and withdrawal. A multi-omics dataset of encompassing different...
Medulloblastoma (MB) is the most common malignant brain tumor in children. Patients with MYC-amplified Group 3 MBs exhibit particularly poor survival rates even after intensive therapy, and surviving patients often suffer from long-term sequelae. Poor sequelae call for new therapeutic strategies, such as targeted therapy options. We have previously shown that are sensitive to class I histone deacetylase (HDAC) inhibition. Here we investigate possible combinatorial treatment HDACi PLK1i....
Abstract Pediatric low-grade gliomas, a diverse group of WHO grade 1 and 2 glial or glioneural tumors, comprise the most common category primary brain tumors in children. The majority these are driven by alterations MAPK pathway, making them principle susceptible to MAPKi therapy. While patients often benefit from during treatment, tumor rebound may occur once treatment is stopped, constituting significant clinical challenge. BT-40, patient-derived cells with molecular features pleomorphic...
Selective targeting of N-Myc-driven Sonic hedgehog (SHH) medulloblastoma has been a challenge for many years and, despite decades research, few targeted therapy opportunities exist. Recently, Kuzuoglu-Ozturk et al. characterized the translatome as promising therapeutic target. The study showed that N-Myc controls subset members protein folding machinery could be inhibited pharmacologically and validated Hsp70 functions required progression in vitro vivo.
High-risk medulloblastoma (MB) remains a deadly disease with poor overall survival despite aggressive multi-modal treatment. Survivors suffer from important treatment-associated morbidity. Patients Group 3 MB tumors amplification or high expression of the transcription factor MYC have particularly outcome. Previously we shown that amplified cell lines are highly susceptible to pan- and class I-selective histone deacetylase (HDAC) inhibitor We here explore potentially sensitizing effect HDAC...
High-risk medulloblastoma (MB) is a deadly disease with poor overall survival despite aggressive multi-modal treatment including surgery, irradiation and chemotherapy. Survivors suffer from important treatment-associated morbidity. Patients Group 3 MB tumors an amplification or high expression of the transcription factor MYC show particularly outcome. We have previously shown that amplified cell lines are highly susceptible to pharmacological inhibition class I histone deacetylases (HDACs)...
High-risk medulloblastoma (MB) is a deadly disease with poor overall survival. Survivors suffer from severe treatment-associated morbidity. Patients Group 3 MB an amplification of MYC show particularly outcome. Therefore novel therapies tailored to this subgroup are urgently needed. We have previously shown that amplified cell lines highly susceptible inhibition class I histone deacetylases (HDACs), including HDAC2. here explore the functional interaction HDAC2 and MYC. Chromatin...
Abstract Medulloblastoma (MB) is one of the common malignant brain tumors in children. Patients with MYC-amplified Group 3 MBs exhibit particularly poor survival rates even after intensive therapy. Surviving patients often suffer from long-term side effects. This calls for new therapeutic strategies, such as targeted therapy options. The sensitivity to class I histone deacetylase (HDAC) inhibition was previously shown. In order elucidate potential combination partners, we have identified...
Abstract Patients with MYC-driven Group 3 medulloblastoma (MB) show particularly poor outcome. It was previously shown that MBs are highly sensitive to class I histone deacetylase inhibition (HDACi). We studied the molecular effects of HDACi entinostat in MB cells identify potentially synergistic drug combinations, prioritizing clinical availability enable translation. Gene expression profiles MYC-amplified group cell line HD-MB03 treated were analyzed using bioinformatic approaches,...
Abstract INTRODUCTION: Pilocytic astrocytoma (PA) is a mitogen-activated protein kinase (MAPK)-driven disease. Treatment of sub-totally resected PA remains challenging and relapses occur even after MAPK-targeted therapies such as MEK inhibition. Oncogenic activation the MAPK-pathway drives majority cells into oncogene-induced senescence (OIS). OIS might represent complementary vulnerability exploitable by senolytic agents. Here we investigated properties BH3-mimetics in PA. METHODS: Four...
Abstract Background Medulloblastoma (MB) is one of the most common malignant pediatric CNS tumors. Patients with Group 3 MBs harboring MYC amplification exhibit low survival rates. Surviving patients suffer from therapy-induced sequelae, which calls for new targeted therapy strategies. We and others have previously shown sensitivity MYC-amplified MB to class I histone deacetylase (HDAC) inhibition. After demonstrating that target gene PLK1 significantly downregulated upon HDACi treatment, we...