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.
Significance Bromodomain and extraterminal (BET) proteins bind acetylated proteins, including histones, and regulate transcription. Interestingly, inhibitors of BET proteins (BETi) can block cancer cell proliferation and induce apoptosis in a wide range of tumor types. To date many of the effects of BETi have been attributed to transcriptional suppression of genes like the MYC oncogene. We show that genetically-engineered Myc-induced lymphoma mouse models are highly sensitive to BETi without MYC transcription being suppressed. Our data suggest broad effects on transcription by BETi including a set of genes being induced. Here a genetic and functional link between BET proteins and histone deacetylases is unraveled that opens up avenues for combination therapies against cancer.
Purpose: Based on the clinical relevance of the chemokine receptor 4 (CXCR4) as a molecular target in cancer and on the success of [ 68 Ga]pentixafor as an imaging probe for high-contrast visualization of CXCR4-expression, the spectrum of clinical CXCR4-targeting was expanded towards peptide receptor radionuclide therapy (PRRT) by the development of [ 177 Lu]pentixather.Experimental design: CXCR4 affinity, binding specificity, hCXCR4 selectivity and internalization efficiency of [ 177 Lu]pentixather were evaluated using different human and murine cancer cell lines.Biodistribution studies (1, 6, 48, 96h and 7d p.i.) and in vivo metabolite analyses were performed using Daudi-lymphoma bearing SCID mice.Extrapolated organ doses were cross-validated with human dosimetry (pre-therapeutic and during [ 177 Lu]pentixather PRRT) in a patient with multiple myeloma (MM).Results: [ 177 Lu]pentixather binds with high affinity, specificity and selectivity to hCXCR4 and shows excellent in vivo stability.Consequently, and supported by >96% plasma protein binding and a logP=-1.76,delaying whole-body clearance of [ 177 Lu]pentixather, tumor accumulation was high and persistent, both in the Daudi model and the MM patient.Tumor/background ratios (7d p.i.) in mice were 499±202, 33±7, 4.0±0.8 and 116±22 for blood, intestine, kidney and muscle, respectively.In the patient, high tumor/kidney and tumor/liver dose ratios of 3.1 and 6.4 were observed during [ 177 Lu]pentixather PRRT (7.8 GBq), with the kidneys being the dose-limiting organs.Conclusions: [ 177 Lu]pentixather shows excellent in vivo CXCR4-targeting characteristics and a suitable pharmacokinetic profile, leading to high tumor uptake and retention and thus high radiation doses to tumor tissue during PRRT, suggesting high clinical potential of this [ 68 Ga]pentixafor/[ 177 Lu]pentixather based CXCR4-targeted theranostic concept.
SDF1α-induced chemotaxis of JAK2-V617F-positive cells is dependent on Bruton tyrosine kinase and its downstream targets PI3K/AKT, PLCγ1 and RhoA JAK2-V617F is present in nearly 95% of patients with polycythemia vera and 50-60% of those with essential thrombocythemia or primary myelofibrosis. 1 In addition to erythrocytosis, thrombocytosis and bone marrow fibrosis (as in polycythemia vera, essential thrombocythemia, and primary myelofibrosis, respectively), the clinical course of patients with myeloproliferative neoplasia (MPN) is characterized by increased risks of thrombosis, splenomegaly and an inflammatory response syndrome. 2,3Clinical studies of JAK kinase inhibitors have shown that these agents can produce considerable improvements of splenomegaly, constitutive symptoms, and overall survival in MPN patients. 3However, the therapeutic response is often limited and short-lived.In addition, transformation to acute leukemia remains a major problem.It is, therefore, essential to identify novel nodes of constitutive JAK2-V617F signaling and to develop better approaches to the therapy of these neoplasias. 4Downstream of JAK2-V617F, NFκB signaling (p65) is constitutively active and regulates expression of CXCL10 in MPN. 5 In bortezomib-resistant multiple myeloma cells 6 and in acute myeloid leukemia cells with MLL-AF9 rearrangements, 7 constitutively active NFκB drives the expression of Bruton tyrosine kinase (BTK).Of note, it was found that BTK interacted with erythropoietin receptor-JAK2 and was tyrosine phosphorylated in response to treatment with erythropoietin. 8These observations led us to investigate whether JAK2-V617F kinase also induces BTK expression (via p65) and activation and to characterize its physiological relevance in JAK2-V617F-positive cells.To investigate whether BTK is activated by JAK2-V617F, we used 32D myeloid progenitor cells ectopically expressing human erythropoietin receptor and JAK2wildtype (32D JAK2-WT) or JAK2-V617F (32D JAK2-V617F). 9Tyrosine phosphorylation of BTK was indeed elevated in whole cell lysates of 32D JAK2-V617F cells compared to the level in 32D JAK2-WT cells (Figure 1A).Consistent with this finding, erythropoietin additionally induced BTK phosphorylation in 32D JAK2-WT cells (Online Supplementary Figure S1A).Of note, BTK was overexpressed in 32D JAK2-V617F cells.In line with our
The purpose of this study was to evaluate prevalence, progression, treatment, and outcome of silent coronary artery disease (CAD) in asymptomatic patients with diabetes (DM) at high coronary risk. Despite the close association of diabetes and CAD, general CAD screening in asymptomatic patients with DM is discouraged even though outcome data in patients at high coronary risk are lacking. Prospective multicenter outcome study—with a pilot randomized treatment substudy. The study comprised 400 asymptomatic patients with DM (type 2) without history or symptoms of CAD at high CAD risk. They underwent clinical evaluation and myocardial perfusion single-photon emission computed tomography (MPS) at baseline and after 2 years. Patients with normal MPS received usual care; those with abnormal MPS received medical or combined invasive and medical management. An abnormal MPS was found in 87 of 400 patients (22%). In patients with normal MPS, MACE occurred in 2.9% and ischemia or new scar in 3.2%. Patients with abnormal MPS had more MACE (9.8%; hazard ratio: 3.44; 95% confidence interval [CI]: 1.32 to 8.95; p = 0.011) and ischemia or new scar (34.2%; odds ratio: 15.91; 95% CI: 7.24 to 38.03; p < 0.001) despite therapy, resulting in “overt or silent CAD progression” of 35.6% versus 4.6% (odds ratio: 11.53; 95% CI: 5.63 to 24.70; p < 0.001). Patients with abnormal MPS randomized to medical versus invasive-medical strategies had similar event rates (p = 0.215), but more ischemic or new scar findings (54.3% vs. 15.8%; p < 0.001). High-risk asymptomatic patients with DM and normal MPS (78%) have a low rate of first manifestations of CAD. Patients with abnormal MPS at baseline (22%) have a 7-fold higher rate of progression to “overt or silent CAD,” despite therapy. Randomized patients’ outcomes suggest that a combined invasive and medical strategy for silent CAD may reduce scintigraphic but not symptomatic CAD progression versus medical therapy alone. (Trial of Invasive versus Medical therapy of Early coronary artery disease in Diabetes Mellitus ISRCTN87953632).
