A5029393201- Cancer-related Molecular Pathways
- Ubiquitin and proteasome pathways
- Acute Myeloid Leukemia Research
- RNA modifications and cancer
- Chronic Myeloid Leukemia Treatments
- Cancer, Hypoxia, and Metabolism
- Cancer Genomics and Diagnostics
- Chronic Lymphocytic Leukemia Research
- Mast cells and histamine
- Cell death mechanisms and regulation
- Epigenetics and DNA Methylation
- Cannabis and Cannabinoid Research
- Biochemical and Molecular Research
- Monoclonal and Polyclonal Antibodies Research
- RNA Research and Splicing
- PI3K/AKT/mTOR signaling in cancer
- Cancer Research and Treatments
- Lung Cancer Treatments and Mutations
- Eosinophilic Disorders and Syndromes
- Colorectal Cancer Treatments and Studies
- Acute Lymphoblastic Leukemia research
- HIV/AIDS drug development and treatment
- Pancreatic function and diabetes
- Click Chemistry and Applications
- Protein Degradation and Inhibitors
Kantonsspital St. Gallen
2021-2025
University of St. Gallen
2021-2023
University Children's Hospital Tübingen
2008-2022
University of Tübingen
2009-2021
Universitätsklinikum Tübingen
2007-2016
Bernstein Center for Computational Neuroscience Tübingen
2012-2013
Oregon Health & Science University
2005-2012
Marcus (United States)
2007
Portland VA Medical Center
2006
Activating mutations of class III receptor tyrosine kinases (RTK) FLT3, PDGFR and KIT are associated with multiple human neoplasms including hematologic malignancies, for example: systemic mast cell disorders (KIT), non-CML myeloproliferative (PDGFR) subsets acute leukemias (FLT3 KIT). First generation kinase inhibitors (TKI) rapidly being integrated into routine cancer care. However, the expanding spectrum TK-mutations, bioavailability issues emerging problem primary or secondary...
Sunitinib and Sorafenib are protein kinase inhibitors (PKI) approved for treatment of patients with advanced renal cell cancer (RCC). However, long-term remissions RCC have only been observed after IL-2 treatment, which underlines the importance antitumor immune responses in patients. Because PKI, besides affecting tumor cells, also may inhibit signaling effector we determined how influence immunity. We found that cytotoxicity cytokine production resting IL-2-activated PBMC inhibited by...
Dysregulation of the PI3Kinase/AKT pathway is involved in pathogenesis many human malignancies. In acute leukemia, AKT frequently activated, however mutations PI3K/AKT are uncommon. some cases, constitutive activation can be linked to gain-of-function tyrosine kinase (TK) upstream pathway. Inhibitors attractive candidates for cancer drug development, but so far clinical efficacy PI3K inhibitors against various neoplasms has been moderate. Furthermore, specific MTORC1 inhibitors, acting...
The ASPP2 (also known as 53BP2L) tumor suppressor is a proapoptotic member of family p53 binding proteins that functions in part by enhancing p53-dependent apoptosis via its C-terminal p53-binding domain. Mounting evidence also suggests harbors important nonapoptotic p53-independent functions. Structural studies identify small G protein Ras-association domain the N terminus. Because Ras-induced senescence barrier to formation normal cells, we investigated whether could bind Ras and stimulate...
ASPP1 (PPP1R13B) belongs to a family of p53-binding proteins and enhances apoptosis by stimulation p53-transactivation selected proapoptotic target genes. It is preferentially expressed in hematopoietic stem cells (HSC) together with p53 preserves the genomic integrity HSC pool. Consequently, dysfunction has been associated malignant transformation development acute lymphoblastic leukemias lymphomas - whereas methylation promoter region linked reduced transcription ultimately attenuated...
The expression of ASPP2 (53BP2L), a proapoptotic member family p53-binding proteins, is frequently suppressed in many human cancers. Accumulating evidence suggests that inhibits tumor growth; however, the mechanisms by which suppresses formation remain to be clarified. To study this, we targeted allele mouse replacing exons 10-17 with neoR gene. ASPP2(-/-) mice were not viable because an early embryonic lethal event. Although ASPP2(+/-) appeared developmentally normal, they displayed...
It has been previously demonstrated in several cancer models, that Dronabinol (THC) may have anti-tumor activity--however, controversial data exists for acute leukemia. We anecdotal evidence THC contributed to disease control a patient with undifferentiated leukemia.To test this hypothesis, we evaluated the antileukemic efficacy of leukemia cell lines and native blasts cultured ex vivo. Expression analysis CB1/2 receptors was performed by Western immunoblotting flow cytometry. CB-receptor...
Abstract Introduction: Despite tremendous efforts and new therapeutics, acute myeloid leukemia (AML) remains difficult to treat therapy outcome is far from satisfactory for many patients. We have recently identified a novel, oncogenic isoform of the tumor suppressor ASPP2, named ASPP2k, which expressed in >50% AMLs, demonstrated that deregulation ASPP2/ASPP2k - p53 axis associates with drug resistance more aggressive biology. now show ASPP2k drives leukemic transformation disease...
Abstract ASPP2 is a tumor suppressor, originally characterized as direct p53-binding protein. More recently, was shown to also directly interact with BCL-2 and NFkB, putting in central position orchestrate major cancer related pathways. In this context, we have recently reported the identification of novel, oncogenic isoform ASPP2, named ASPP2kappa (k), which highly frequently expressed TNBC. As ASPP2k by loss p53- well partial NFkB-binding sites, its expression impairs pathways controlling...
AML remains a difficult disease to treat. Despite response induction chemotherapy, most patients ultimately relapse. Further, among elderly patients, aggressive therapy options are often limited due other medical conditions and decreased tolerance of these conventional chemotherapy. Internal tandem duplications (ITD) the FLT3 juxtamembrane domain occur in 20-30% predict poor outcome. First clinical data with inhibitor tandutinib demonstrated antileukemic activity approximately half -...
The p53 pathway is a central mediator of the apoptotic response. ASPP2/53BP2L (apoptosis-stimulating protein 2, also known as 53BP2L) enhances apoptosis through selective stimulation transactivation proapoptotic target genes. Although Rb/E2F regulates transcription, complex mechanisms controlling levels and function remain unknown. We now report that proteasomal degradation modulates function. Treatment cells with inhibitors, including clinically utilized inhibitor bortezomib, increases but...
Inactivation of the p53 pathway is a universal event in human cancers and promotes tumorigenesis resistance to chemotherapy. Inactivating mutations are uncommon non-complex karyotype leukemias, thus p53-pathway must be inactivated by other mechanisms. The Apoptosis Stimulating Protein p53-2 (ASPP2) damage-inducible p53-binding protein that enhances apoptosis at least part through p53-mediated pathway. We have previously shown, ASPP2 an independent haploinsufficient tumor suppressor vivo....
Activating D816 mutations of the class III receptor tyrosine kinase KIT are associated with majority patients systemic mastocytosis (SM), but also core binding factor (CBF) AML, making attractive therapeutic targets for treatment these cancers. Crenolanib is a potent and selective inhibitor wild-type as well mutant isoforms kinases FLT3 PDGFRα/β. Notably, crenolanib inhibits constitutively active mutant-FLT3 resulting from amino acid substitutions aspartic at codon 835, which homologous to...
BackgroundApoptosis-stimulating Protein of TP53-2 (ASPP2) is a tumor suppressor enhancing TP53-mediated apoptosis via binding to the TP53 core domain. mutations found in cancers disrupt ASPP2 binding, arguing for an important role suppression. We now identify oncogenic splicing variant, ASPP2κ, with high prevalence acute leukemia.MethodsAn mRNA screen detect variants was performed and ASPP2κ validated using isoform-specific PCR approaches. Translation into genuine protein isoform evaluated...
BackgroundOverriding the differentiation blockage in acute myeloid leukemia (AML) is most successful mode-of-action therapy – now curing vast majority of patients with promyelocytic (APL) using all-trans retinoic acid (ATRA)-based regimens. Similar approaches other subtypes, such as IDH1/2-mutated AML, are under active investigation. We herein present release upon treatment natural (−)-Δ9-Tetrahydrocannabinol isomer dronabinol vitro and vivo.MethodsCellular maturation were followed two...
// Kerstin M. Kampa-Schittenhelm 1 , Wichard Vogel Irina Bonzheim 2 Falko Fend Marius Horger 3 Lothar Kanz Martin Soekler and Marcus Schittenhelm Department of Oncology, Hematology, Rheumatology, Clinical Immunology Pulmonology, University Hospital Tübingen, Germany Institute Pathology Neuropathology, Reference Center for Hematopathology, Diagnostic Interventional Radiology, Correspondence to: Schittenhelm, email: marcus.schittenhelm@med.uni-tuebingen.de Keywords: CBF AML; KIT; tyrosine...
Abstract The p53 mutation R273H in tumor cells leads to increased glucose uptake, lactic acidosis, and accelerated growth, as was previously shown mice. We here present a patient with mantle cell lymphoma harboring this p53_R273H mutation, whose clinical course is characterized by severe hypoglycemia, aggressive disease.
Background: Based on our pre-clinical data, we hypothesized that sequencing chemotherapy with erlotinib would increase the tumor response rate in patients metastatic colorectal cancer. Patients and Methods: A phase II trial (planned n=58) using second-line therapy for cancer either oxaliplatin-based (mFOLFOX6) or irinotecan-based (FOLFIRI) combination 100 mg daily days 3-8 after each infusion (days 1 2) every 14 days. The primary endpoint was compared to historical rate. Results:...
Abstract BACKGROUND GB is the most common, aggressive primary brain tumor with a deleterious prognosis. ASPP2 suppressor, directly interacting p53. We recently identified dominant-negative isoform of ASPP2, named ASPP2κ, lacking important p53 binding sites and show that ASPP2κ highly expressed functionally active in glioblastoma, affecting all classical hallmarks cancer. MATERIAL AND METHODS Grade IV glioma (n=46) were assessed for expression. Isogenic models, stably suppressing or...