title: NEMO-binding domain peptide inhibits constitutive NF-κB activity and reduces tumor burden in a canine model of relapsed, refractory diffuse large B-cell lymphoma.
abstract: OBJECTIVE
  Activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive, poorly chemoresponsive lymphoid malignancy characterized by constitutive canonical NF-κB activity that promotes lymphomagenesis and chemotherapy resistance via overexpression of antiapoptotic NF-κB target genes. Inhibition of the canonical NF-κB pathway may therefore have therapeutic relevance in ABC-DLBCL. Here, we set out to determine whether dogs with spontaneous DLBCL have comparative aberrant constitutive NF-κB activity and to determine the therapeutic relevance of NF-κB inhibition in dogs with relapsed, resistant DLBCL.
  
  
  METHODS
  Canonical NF-κB activity was evaluated by electrophoretic mobility shift assays and immunoblot analyses, and NF-κB target gene expression was measured by quantitative real time PCR. Primary malignant canine B lymphocytes were treated with the selective IKK complex inhibitor NF-κB essential modulator-binding domain (NBD) peptide and evaluated for NF-κB activity and apoptosis. NBD peptide was administered intranodally to dogs with relapsed B-cell lymphoma and NF-κB target gene expression and tumor burden were evaluated pre- and post-treatment.
  
  
  RESULTS
  Constitutive canonical NF-κB activity and increased NF-κB target gene expression were detected in primary DLBCL tissue. NBD peptide inhibited this activity and induced apoptosis of primary malignant B cells in vitro. Intratumoral injections of NBD peptide to dogs with relapsed DLBCL inhibited NF-κB target gene expression and reduced tumor burden.
  
  
  CONCLUSIONS
  This work shows that dogs with spontaneous DLBCL represent a clinically relevant, spontaneous, large animal model for human ABC-DLBCL and shows the therapeutic relevance of NF-κB inhibition in the treatment of ABC-DLBCL. These results have important translational relevance for ABC-DLBCL treatment in human patients.
authors: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6010, USA.
authors: Anita
authors: A
authors: Gaurnier-Hausser
authors: Reema
authors: R
authors: Patel
authors: Albert S
authors: AS
authors: Baldwin
authors: Michael J
authors: MJ
authors: May
authors: Nicola J
authors: NJ
authors: Mason
references: J Comp Pathol. 1997 Jul;117(1):35-59
references: 9263843
references: Nature. 2000 Feb 3;403(6769):503-11
references: 10676951
references: J Vet Intern Med. 2006 Sep-Oct;20(5):1085-92
references: 17063700
references: Nat Immunol. 2002 Mar;3(3):221-7
references: 11875461
references: Nature. 2009 Jun 4;459(7247):717-21
references: 19412164
references: Nature. 2010 Jan 7;463(7277):88-92
references: 20054396
references: Cold Spring Harb Perspect Biol. 2010 Jan;2(1):a000216
references: 20182598
references: J Biol Chem. 2009 Oct 2;284(40):27596-608
references: 19666475
references: Crit Care Med. 2005 Jun;33(6):1384-91
references: 15942360
references: Nat Med. 2004 Jun;10(6):617-24
references: 15156202
references: Nat Rev Mol Cell Biol. 2007 Jan;8(1):49-62
references: 17183360
references: Br J Cancer. 2003 Oct 20;89(8):1530-7
references: 14562028
references: J Biol Chem. 2002 Nov 29;277(48):45992-6000
references: 12244103
references: Nat Med. 1999 Jan;5(1):56-63
references: 9883840
references: Chromosome Res. 2008;16(1):145-54
references: 18293109
references: J Exp Med. 2009 Oct 26;206(11):2313-20
references: 19841089
references: Clin Cancer Res. 2005 Jan 1;11(1):28-40
references: 15671525
references: Oncogene. 2006 Oct 30;25(51):6680-4
references: 17072321
references: Science. 2002 Nov 8;298(5596):1241-5
references: 12424381
references: Vet Clin North Am Small Anim Pract. 2007 Nov;37(6):1023-32; v
references: 17950880
references: Arthritis Rheum. 2005 Mar;52(3):951-8
references: 15751079
references: Nature. 2005 Dec 8;438(7069):803-19
references: 16341006
references: Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13102-7
references: 12232044
references: J Exp Med. 2001 Dec 17;194(12):1861-74
references: 11748286
references: Cell Mol Life Sci. 2008 Nov;65(22):3564-91
references: 18668204
references: Nat Rev Cancer. 2008 Feb;8(2):147-56
references: 18202698
references: Oncogene. 2006 Oct 30;25(51):6887-99
references: 17072334
references: Science. 2000 Sep 1;289(5484):1550-4
references: 10968790
references: Oncogene. 2006 Oct 30;25(51):6717-30
references: 17072324
references: Cancer Metastasis Rev. 1990 Sep;9(2):125-36
references: 2253312
references: Biochem Pharmacol. 2005 Sep 1;70(5):700-13
references: 16023083
references: Blood. 2007 Jun 1;109(11):4930-5
references: 17299093
references: Science. 2008 Mar 21;319(5870):1676-9
references: 18323416
references: J Clin Invest. 2007 Apr;117(4):889-901
references: 17380205
references: Cell Cycle. 2007 Sep 15;6(18):2284-92
references: 17890907
references: Blood. 2005 Aug 15;106(4):1164-74
references: 15855278
references: Mol Ther. 2005 Dec;12(6):1072-82
references: 16226919
references: Int J Cancer. 2004 Sep 20;111(5):679-92
references: 15252836
references: Surgery. 2002 Aug;132(2):127-34
references: 12219002
references: Cancer Res. 2009 Mar 15;69(6):2365-74
references: 19258503
references: Nature. 2005 Apr 28;434(7037):1138-43
references: 15858576
references: Cancer Lett. 2009 Feb 18;274(2):331-6
references: 19004544
references: Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20798-803
references: 19104039
references: Blood. 2005 Aug 15;106(4):1392-9
references: 15870177