Filtern
Volltext vorhanden
- ja (14)
Gehört zur Bibliographie
- ja (14)
Dokumenttyp
- Artikel / Aufsatz in einer Zeitschrift (14) (entfernen)
Sprache
- Englisch (14) (entfernen)
Schlagworte
- CXCR4 (3)
- chemokine receptor (3)
- positron emission tomography (3)
- HNSCC (2)
- in vivo imaging (2)
- lymphoma (2)
- microenvironment (2)
- mutations (2)
- Activation (1)
- Bruton Tyrosine Kinase (1)
- B‐cell lymphoma (1)
- C-Myc (1)
- CXCR4/SDF-1 (1)
- DEL(5Q) (1)
- DLBCL (1)
- DOTATOC (1)
- EGFR (1)
- FDG PET/CT (1)
- FLT-PET (1)
- Ibrutinib (1)
- Ligand (1)
- MDS (1)
- MYC (1)
- Malignancies (1)
- Multiple Myeloma (1)
- NF-KAPPA-B (1)
- PCI-32765 (1)
- PET/CT (1)
- PRRT (1)
- Pathway (1)
- Positronen-Emissions-Tomografie (1)
- Proliferation (1)
- Rho-GTPases (1)
- SSTR (1)
- SphK1 (1)
- TP53 mutations (1)
- Targeted Therapies (1)
- Tumor Microenvironment (1)
- USP9X (1)
- XIAP (1)
- [18F]Fluorodeoxythymidine (1)
- [\(^{68}\)Ga]Pentixafor (1)
- \(^{68}\)Ga-Pentixafor (1)
- activation (1)
- acute myeloid leukemia (1)
- apoptosis (1)
- apoptosis, Myc (1)
- aurora kinase A polymorphism (1)
- aurorakinase B (1)
- autologous transplantation (1)
- azacitidine (1)
- bone disease (1)
- cancer (1)
- cancer genetics (1)
- cancer genomics (1)
- cancer therapy (1)
- cells (1)
- cetuximab (1)
- chemokine receptor-4 (1)
- cleavage (1)
- combined immunodeficiency (1)
- cycle (1)
- endothelial cells (1)
- glioblastoma (1)
- glutaminase inhibition (1)
- growth (1)
- helper T-cells (1)
- imaging (1)
- involvement (1)
- karyotype (1)
- leukemia (1)
- lymphoid-tissue (1)
- malignancies (1)
- messenger RNA (1)
- mice (1)
- mitosis (1)
- multiple myeloma (1)
- myeloma (1)
- neuroendocrine tumor (1)
- niche (1)
- p53 expression (1)
- peptide receptor radionuclide therapy (1)
- positron emission tomography/computed tomography (1)
- prognosis (1)
- prognostic value (1)
- radiation (1)
- radiation-induced migration (1)
- roquin (1)
- scoring system (1)
- stem-cells (1)
- survival (1)
- target (1)
- therapeutic target (1)
- translational research (1)
- ubiquitin (1)
Institut
- Pathologisches Institut (14) (entfernen)
Multiple Myeloma (MM) is an incurable hematological malignancy affecting millions of people worldwide. As in all tumor cells both glucose and more recently glutamine have been identified as important for MM cellular metabolism, however there is some dispute as to the role of glutamine in MM cell survival. Here we show that the small molecule inhibitor compound 968 effectively inhibits glutaminase and that this inhibition induces apoptosis in both human multiple myeloma cell lines (HMCLs) and primary patient material. The HMCL U266 which does not express MYC was insensitive to both glutamine removal and compound 968, but ectopic expression of MYC imparted sensitivity. Finally, we show that glutamine depletion is reflected by rapid loss of MYC protein which is independent of MYC transcription and post translational modifications. However, MYC loss is dependent on proteasomal activity, and this loss was paralleled by an equally rapid induction of apoptosis. These findings are in contrast to those of glucose depletion which largely affected rates of proliferation in HMCLs, but had no effects on either MYC expression or viability. Therefore, inhibition of glutaminolysis is effective at inducing apoptosis and thus serves as a possible therapeutic target in MM.
Disclosing the CXCR4 expression in lymphoproliferative diseases by targeted molecular imaging
(2015)
Chemokine ligand-receptor interactions play a pivotal role in cell attraction and cellular trafficking, both in normal tissue homeostasis and in disease. In cancer, chemokine receptor-4 (CXCR4) expression is an adverse prognostic factor. Early clinical studies suggest that targeting CXCR4 with suitable high-affinity antagonists might be a novel means for therapy. In addition to the preclinical evaluation of [\(^{68}\)Ga]Pentixafor in mice bearing human lymphoma xenografts as an exemplary CXCR4-expressing tumor entity, we report on the first clinical applications of [\(^{68}\)Ga]Pentixafor-Positron Emission Tomography as a powerful method for CXCR4 imaging in cancer patients. [\(^{68}\)Ga]Pentixafor binds with high affinity and selectivity to human CXCR4 and exhibits a favorable dosimetry. [\(^{68}\)Ga]Pentixafor-PET provides images with excellent specificity and contrast. This non-invasive imaging technology for quantitative assessment of CXCR4 expression allows to further elucidate the role of CXCR4/CXCL12 ligand interaction in the pathogenesis and treatment of cancer, cardiovascular diseases and autoimmune and inflammatory disorders.
Drug resistance is a significant obstacle in cancer treatment and therefore a frequent subject of research. Developed or primary resistance limits the treatment success of inhibitors of the B cell receptor (BCR) pathway in mantle cell lymphoma (MCL) patients. Recent research has highlighted the role of the nuclear factor-kappa B (NF kappa B) pathway in the context of resistance to BCR inhibitors in MCL. In this study, we analyzed the dependency of MCL cell lines on NF kappa B signaling and illustrated the ability of CD40L to activate the alternative NF kappa B pathway in MCL. This activation leads to independency of classical NF kappa B signaling and results in resistance to BCR inhibitors. Therefore, ligands (such as CD40L) and their activation of the alternative NF kappa B pathway have a major impact on the drug response in MCL. Furthermore, this study indicates a protective role for cells expressing specific ligands as microenvironmental niches for MCL cells and underlines the significance of therapeutically targeting alternative NF kappa B signaling in MCL.
Chemokine receptor-4 (CXCR4) has been reported to be overexpressed in glioblastoma (GBM) and to be associated with poor survival. This study investigated the feasibility of non-invasive CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using the radiolabelled chemokine receptor ligand \(^{68}\)Ga-Pentixafor.
15 patients with clinical suspicion on primary or recurrent glioblastoma (13 primary, 2 recurrent tumors) underwent \(^{68}\)Ga-Pentixafor-PET/CT for assessment of CXCR4 expression prior to surgery. O-(2-\(^{18}\)F-fluoroethyl)-L-tyrosine (\(^{18}\)F-FET) PET/CT images were available in 11/15 cases and were compared visually and semi-quantitatively (SUV\(_{max}\), SUV\(_{mean}\)). Tumor-to-background ratios (TBR) were calculated for both PET probes. \(^{68}\)Ga-Pentixafor-PET/CT results were also compared to histological CXCR4 expression on neuronavigated surgical samples.
\(^{68}\)Ga-Pentixafor-PET/CT was visually positive in 13/15 cases with SUV\(_{mean}\) and SUV\(_{max}\) of 3.0±1.5 and 3.9±2.0 respectively. Respective values for \(^{18}\)F-FET were 4.4±2.0 (SUV\(_{mean}\)) and 5.3±2.3 (SUV\(_{max}\)). TBR for SUV\(_{mean}\) and SUV\(_{max}\) were higher for \(^{68}\)Ga-Pentixafor than for \(^{18}\)F-FET (SUV\(_{mean}\) 154.0±90.7 vs. 4.1±1.3; SUV\(_{max}\) 70.3±44.0 and 3.8±1.2, p<0.01), respectively. Histological analysis confirmed CXCR4 expression in tumor areas with high \(^{68}\)Ga-Pentixafor uptake; regions of the same tumor without apparent \(^{68}\)Ga-Pentixafor uptake showed no or low receptor expression.
In this pilot study, \(^{68}\)Ga-Pentixafor retention has been observed in the vast majority of glioblastoma lesions and served as readout for non-invasive determination of CXCR4 expression. Given the paramount importance of the CXCR4/SDF-1 axis in tumor biology, \(^{68}\)Ga-Pentixafor-PET/CT might prove a useful tool for sensitive, non-invasive in-vivo quantification of CXCR4 as well as selection of patients who might benefit from CXCR4-directed therapy.