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Shakir M.,University of Pittsburgh | Tang D.,University of Pittsburgh | Zeh H.J.,University of Pittsburgh | Tang S.W.,University of Pittsburgh | And 4 more authors.

Novel therapies need to be developed for patients with pancreatic cancer because of the poor outcomes of current regimens. Pancreatic cancer cells respond to the C-X-C chemokine receptor type 4 (CXCR4)/C-X-C chemokine receptor type 7 (CXCR7)/C-X-C motif chemokine 12 (CXCL12)/high-mobility group box 1 signaling axis and this axis presents a novel target for therapy. C-X-C motif chemokine 12 stimulates CXCR4/CXCR7-bearing cells in a paracrine manner. C-X-C chemokine receptor type 4 and CXCR7 are transmembrane G protein-coupled receptors that, upon interaction with ligand CXCL12, activate downstream protein kinases that promote a more aggressive behavior. C-X-C chemokine receptor type 4 is expressed on most pancreatic cancer cells, whereas CXCR7 is primarily expressed on tumor-associated endothelium. High-mobility group box 1 promotes the CXCR4 and CXCL12 interaction, promoting angiogenesis and lymphangiogenesis. Hypoxia-inducible factor 1 is a potent stimulator of CXCR4 and CXCL12 expression, promoting more aggressive behavior. This receptor/ligand interaction can be disrupted by CXCR4 antagonists available and in clinical use to harvest bone marrow stem cells. Novel imaging strategies are now being developed at several centers to evaluate response to therapy and identify early recurrence. Thus, the CXCR4/CXCR7/CXCL12 interaction plays a critical role in cancer cell progression, proliferation, invasion, as well as metastasis and is a suitable target for therapy, imaging, as well as development of novel diagnostics. © 2015 Wolters Kluwer Health, Inc. All rights reserved. Source

Meng J.,Molecular Imaging Laboratory | Liu Y.,Angimmune LLC | Gao S.,Angimmune LLC | Lin S.,Molecular Imaging Laboratory | And 3 more authors.
Cancer Biology and Therapy

EGFR and EGFRvIII are overexpressed in various types of cancer, serving as optimal targets for cancer therapy. Capitalizing on the high specificity of humanized antibody 806 (mAb806) to the EGFR and EGFRvIII overexpressed in cancer, we designed and generated a bivalent recombinant immunotoxin (RIT, DT390-BiscFv806) by fusing the mAb806-derived bivalent single-chain variable fragment with a diphtheria toxin fragment, DT390. In vitro, DT390-BiscFv806 efficiently internalized into the cells and exhibited high cytotoxicity against the U87 glioblastoma cells and the EGFRvIII-transfected U87 (U87-EGFRvIII) cells with a half maximal inhibition concentration (IC50) of 1.47 nM and 2.26 × 10−4 nM, respectively. Notably, DT390-BiscFv806 was 4 orders of magnitude more potent against the U87-EGFRvIII cells than against the parent U87 cells. The cytotoxicity against a group of 6 head and neck squamous cell carcinoma cell lines were further analyzed, showing an IC50 ranging from 0.24 nM to 156 nM, depending on the expression level of EGFR/EGFRvIII. In animals, the U87-EGFRvIII tumor xenografts grew extremely faster than the parental U87, and systemic administration of DT390-BiscFv806 significantly inhibited the growth of established U87-EGFRvIII and U87 tumor xenografts, showing a growth inhibition rate of 76.3% (59.82–96.2%) and 59.4% (31.5–76.0%), respectively. In pathology, the RIT-treated tumors exhibited a low mitotic activity and a large number of degenerative tumor cells, compared with the control tumors. The results indicate that DT390-BiscFv806 is promising for treatment of various types of cancer, especially for those with high EGFR expression or with EGFR and EGFRvIII co-expression. © 2015 Taylor & Francis Group, LLC. Source

Rerat V.,Catholic University of Louvain | Laurent S.,Molecular Imaging Laboratory | Burtea C.,Molecular Imaging Laboratory | Driesschaert B.,Catholic University of Louvain | And 4 more authors.
Bioorganic and Medicinal Chemistry Letters

Ultrasmall particles of iron oxide (USPIOs) coated with 3,3′-bis(phosphonate)propionic acid were covalently coupled to a home-made Arg-Gly-Asp (RGD) peptidomimetic molecule via a short oligoethyleneglycol (OEG) spacer. The conjugation rate was measured by X-ray photoelectron spectroscopy (XPS). The particle size and magnetic characteristics were kept. Our novel conjugate targeted efficiently Jurkat cells (increase of 229% vs the control). © 2010 Elsevier Ltd. All rights reserved. Source

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