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Oklahoma City, MA, United States

Wang S.,Georgetown University | Astsaturov I.A.,Fox Chase Cancer Center | Bingham C.A.,Fox Chase Cancer Center | McCarthy K.M.,Fox Chase Cancer Center | And 9 more authors.
Cancer Immunology, Immunotherapy | Year: 2012

Toll-like receptors are potent activators of the innate immune system and generate signals leading to the initiation of the adaptive immune response that can be utilized for therapeutic purposes. We tested the hypothesis that combined treatment with a Toll-like receptor agonist and an antitumor monoclonal antibody is effective and induces host-protective antitumor immunity. C57BL/6 human mutated HER2 (hmHER2) transgenic mice that constitutively express kinase-deficient human HER2 under control of the CMV promoter were established. These mice demonstrate immunological tolerance to D5-HER2, a syngeneic human HER2-expressing melanoma cell line. This human HER2-tolerant model offers the potential to serve as a preclinical model to test both antibody therapy and the immunization potential of human HER2-targeted therapeutics. Here, we show that E6020, a Toll-like receptor-4 (TLR4) agonist effectively boosted the antitumor efficacy of the monoclonal antibody trastuzumab in immunodeficient C57BL/6 SCID mice as well as in C57BL/6 hmHER2 transgenic mice. E6020 and trastuzumab co-treatment resulted in significantly greater inhibition of tumor growth than was observed with either agent individually. Furthermore, mice treated with the combination of trastuzumab and the TLR4 agonist were protected against rechallenge with human HER2-transfected tumor cells in hmHER2 transgenic mouse strains. These findings suggest that combined treatment with trastuzumab and a TLR4 agonist not only promotes direct antitumor effects but also induces a host-protective human HER2-directed adaptive immune response, indicative of a memory response. These data provide an immunological rationale for testing TLR4 agonists in combination with antibody therapy in patients with cancer. © 2011 Springer-Verlag. Source


Smith J.A.,University of California at Santa Barbara | Wilson L.,University of California at Santa Barbara | Azarenko O.,University of California at Santa Barbara | Zhu X.,Eisai Research Institute andover | And 4 more authors.
Biochemistry | Year: 2010

Eribulin mesylate (E7389), a synthetic analogue of the marine natural product halichondrin B, is in phase III clinical trials for the treatment of cancer. Eribulin targets microtubules, suppressing dynamic instability at microtubule plus ends through an inhibition of microtubule growth with little or no effect on shortening [Jordan,M. A., et al. (2005) Mol. Cancer Ther. 4, 1086-1095]. Using [3H]eribulin, we found that eribulin binds soluble tubulin at a single site; however, this binding is complex with an overall Kd of 46 μM, but also showing a real or apparent very high affinity (Kd = 0.4 μM) for a subset of 25% of the tubulin. Eribulin also binds microtubules with a maximum stoichiometry of 14.7 ± 1.3 molecules per microtubule (Kd = 3.5 μM), strongly suggesting the presence of a relatively high-affinity binding site at microtubule ends. At 100 nM, the concentration that inhibits microtubule plus end growth by 50%, we found that one molecule of eribulin is bound per two microtubules, indicating that the binding of a single eribulin molecule at a microtubule end can potently inhibit its growth. Eribulin does not suppress dynamic instability at microtubule minus ends. Preincubation of microtubules with 2 or 4 μM vinblastine induced additional lower-affinity eribulin binding sites, most likely at splayed microtubule ends. Overall, our results indicate that eribulin binds with high affinity to microtubule plus ends and thereby suppresses dynamic instability. © 2010 American Chemical Society. Source


Yoneyama T.,Glycobiology Unit | Yoneyama T.,Hirosaki University | Angata K.,Glycobiology Unit | Angata K.,Japan National Institute of Advanced Industrial Science and Technology | And 5 more authors.
Molecular Biology of the Cell | Year: 2012

Glycans of α-dystroglycan (α-DG), which is expressed at the epithelial cell-basement membrane (BM) interface, play an essential role in epithelium development and tissue organization. Laminin-binding glycans on α-DG expressed on cancer cells suppress tumor progression by attenuating tumor cell migration from the BM. However, mechanisms controlling laminin-binding glycan expression are not known. Here, we used small interfering RNA (siRNA) library screening and identified Fer kinase, a non-receptor-type tyrosine kinase, as a key regulator of laminin-binding glycan expression. Fer overexpression decreased laminin- binding glycan expression, whereas siRNA-mediated down-regulation of Fer kinase increased glycan expression on breast and prostate cancer cell lines. Loss of Fer kinase function via siRNA or mutagenesis increased transcription levels of glycosyltransferases, including protein O-mannosyltransferase 1, β3-N-acetylglucosaminyltransferase 1, and like-acetylglucosaminyltransferase that are required to synthesize laminin-binding glycans. Consistently, inhibition of Fer expression decreased cell migration in the presence of laminin fragment. Fer kinase regulated STAT3 phosphorylation and consequent activation, whereas knockdown of STAT3 increased laminin-binding glycan expression on cancer cells. These results indicate that the Fer pathway negatively controls expression of genes required to synthesize lamininbinding glycans, thus impairing BM attachment and increasing tumor cell migration. © 2012 Yoneyama et al. Source


Singh M.,Novartis | Kazzaz J.,Novartis | Ugozzoli M.,Novartis | Baudner B.,Novartis | And 5 more authors.
Human Vaccines and Immunotherapeutics | Year: 2012

The inclusion of a potent TLR4 immune potentiator to a recombinant antigen vaccine formulation enhances both the magnitude and the breadth of the engendered immune response. One such immune potentiator (TLR4 agonist E6020) was evaluated with recombinant Men B antigens delivered in MF59 sub-micron adjuvant emulsion. The ability of this formulation to enhance serum antibody and bactercidal titers was investigated. The co-delivery of E6020 within MF59 enhanced both the serum and bactericidal titers for Men B antigens and for Men B antigens combined with Men ACWY-CRM conjugate vaccine. The delivery of TLR4 agonist within MF59 emulsion oil droplets leads to a more potent response in comparison to the TLR4 when admixed with MF59 emulsion. © 2012 Landes Bioscience. Source


Lee K.-H.,Dana-Farber Cancer Institute | Lee K.-H.,Harvard University | Liu Y.-J.,Dana-Farber Cancer Institute | Biswas A.,Dana-Farber Cancer Institute | And 4 more authors.
Journal of Biological Chemistry | Year: 2011

Toll-like receptors (TLRs) and nucleotide-binding domain, leucine-rich repeat (NLR) proteins are two major forms of innate immune receptors that trigger inflammatory responses by various biological mechanisms such as cytokine production, recruitment of inflammatory cells, or activation of adaptive immunity. Although the innate immune system is designed to fight against infectious pathogens, excessive activation of TLR or NLR signaling pathways may lead to unwarranted inflammation with hazardous outcomes, including septic shock or inflammatory diseases. As part of the search for effective therapeutics to regulate these responses, here we show that a novel aminosaccharide compound, named DFK1012, inhibits immune responses caused by TLR and NLR activation. Treatment with DFK1012, but not its derivatives DFK845 or DFK846, strongly inhibited pro-inflammatory cytokine production upon stimulation via either TLR or NLR proteins in macrophages. Importantly, we have not observed cytotoxicity in any range of its working concentration. Treatment with DFK1012 did not interfere with TLR- or NLR-induced activation of p38 and JNK, phosphorylation/degradation of IκB, and subsequent nuclear translocation of NF-κB subunit p65, suggesting that the inhibitory activity of DFK1012 is not due to the suppression of downstream signaling. Indeed, DFK1012 did not impair transcription of pro-inflammatory cytokine genes but rather promoted post-translational degradation of pro-inflammatory cytokines. Therefore, DFK1012 is a novel anti-inflammatory compound that drives proteolysis of proinflammatory cytokines induced by TLR and NLR stimulation. DFK1012 may represent a novel class of potential therapeutic agents aimed at the treatment of inflammatory disorders. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc. Source

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