title: Dll4-notch signalling blockade synergizes combined ultrasound-stimulated microbubble and radiation therapy in human colon cancer xenografts.
abstract: Tumour vasculature acts as an essential lifeline for tumour progression and facilitates metastatic spread. Novel vascular targeting strategies aiming to sustain vascular shutdown could potentially induce substantial damage, resulting in a significant tumour growth delay. We investigated the combination of two novel complementary vascular targeting agents with radiation therapy in a strategy aiming to sustain vascular disruption. Experiments were carried out with delta-like ligand 4 (Dll4) blockade (angiogenesis deregulator) treatment administered in combination with a radiation-based vascular destruction treatment in a highly aggressive well-perfused colon cancer tumour line implanted in female athymic nude mice. Tumours were treated with permutations of radiation, ultrasound-stimulated microbubbles (USMB) and Dll4 monoclonal antibody (mAb). Tumour vascular response was assessed with three-dimensional power Doppler ultrasound to measure active flow and immunohistochemistry. Tumour response was assessed with histochemical assays and longitudinal measurements of tumour volume. Our results suggest a significant tumour response in animals treated with USMB combined with radiation, and Dll4 mAb, leading to a synergistic tumour growth delay of up to 24 days. This is likely linked to rapid cell death within the tumour and a sustained tumour vascular shutdown. We conclude that the triple combination treatments cause a vascular shutdown followed by a sustained inhibition of angiogenesis and tumour cell death, leading to a rapid tumour vascular-based 'collapse' and a significant tumour growth delay.
authors.affiliation: Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Departments of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ahmed
authors.initials: A
authors.lastname: El Kaffas
authors.affiliation: Departments of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Joris
authors.initials: J
authors.lastname: Nofiele
authors.affiliation: Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Departments of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Anoja
authors.initials: A
authors.lastname: Giles
authors.affiliation: Department of Oncology Research, MedImmune, Maryland, United States of America.
authors.forename: Song
authors.initials: S
authors.lastname: Cho
authors.affiliation: Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Departments of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stanley K
authors.initials: SK
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Departments of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Czarnota
mesh_terms: D000818:Animals; D016923:Cell Death; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000532:radiotherapy; D004195:Disease Models, Animal; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D045423:Microbubbles; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden; D018615:Ultrasonography, Doppler, Color; D023041:Xenograft Model Antitumor Assays
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D051880:Receptors, Notch; C064045:delta protein
references.citation: J Biol Chem. 2005 Jul 15;280(28):26425-34
references.pmid: 15849201
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3219-24
references.pmid: 17296940
references.citation: PLoS One. 2010 Jun 21;5(6):e11222
references.pmid: 20574535
references.citation: Proc Natl Acad Sci U S A. 2012 Jul 24;109(30):E2033-41
references.pmid: 22778441
references.citation: Int J Radiat Oncol Biol Phys. 2011 Sep 1;81(1):270-6
references.pmid: 21163591
references.citation: Technol Cancer Res Treat. 2012 Oct;11(5):421-32
references.pmid: 22568629
references.citation: Nat Rev Cancer. 2008 Aug;8(8):592-603
references.pmid: 18650835
references.citation: Cancer Res. 2002 Nov 15;62(22):6371-5
references.pmid: 12438217
references.citation: Med Phys. 2012 Jan;39(1):392-8
references.pmid: 22225308
references.citation: Vasc Cell. 2011 Sep 18;3(1):20
references.pmid: 21923938
references.citation: Nature. 2006 Dec 21;444(7122):1083-7
references.pmid: 17183323
references.citation: Cancer Res. 2005 Oct 1;65(19):8690-7
references.pmid: 16204037
references.citation: PLoS One. 2012;7(12):e52307
references.pmid: 23284980
references.citation: Trends Biotechnol. 2012 Dec;30(12):649-58
references.pmid: 23021636
references.citation: Ultrasound Med Biol. 2012 Nov;38(11):1958-69
references.pmid: 22980406
references.citation: Drug Resist Updat. 2012 Jun;15(3):173-82
references.pmid: 22561672
references.citation: J Vasc Res. 2010;47(6):472-80
references.pmid: 20431296
references.citation: Oncologist. 2007 Apr;12(4):465-77
references.pmid: 17470689
references.citation: Cancer Cell. 2005 Aug;8(2):89-91
references.pmid: 16098459
references.citation: Ultrasound Med Biol. 2013 Aug;39(8):1376-87
references.pmid: 23643061
references.citation: J Natl Cancer Inst. 2011 Dec 7;103(23):1778-98
references.pmid: 22010178
references.citation: Trends Mol Med. 2007 Sep;13(9):389-95
references.pmid: 17822956
references.citation: Cancer Res. 2010 Oct 15;70(20):8179-86
references.pmid: 20924105
references.citation: Angiogenesis. 2013 Apr;16(2):443-54
references.pmid: 23314761
references.citation: Nature. 2006 Dec 21;444(7122):1032-7
references.pmid: 17183313
references.citation: Cold Spring Harb Perspect Med. 2012 Mar;2(3):a006486
references.pmid: 22393532
references.citation: Br J Cancer. 2012 Jul 24;107(3):469-76
references.pmid: 22790798
references.citation: J Biochem. 2013 Mar;153(3):243-9
references.pmid: 23293323
references.citation: J Exp Med. 1994 Aug 1;180(2):525-35
references.pmid: 8046331
references.citation: Cancer Res. 2011 Dec 15;71(24):7339-44
references.pmid: 22144472
references.citation: Carcinogenesis. 2000 Mar;21(3):505-15
references.pmid: 10688871
references.citation: Ultrasound Med Biol. 2013 Nov;39(11):1983-90
references.pmid: 23993051
references.citation: Ultrasound Med Biol. 2000 Jan;26(1):1-27
references.pmid: 10687788