2-(&#969;-Carboxyethyl)pyrrole Antibody as a New Inhibitor of Tumor Angiogenesis and Growth.
BACKGROUND
Angiogenesis is a fundamental process in the progression, invasion, and metastasis of tumors. Therapeutic drugs such as bevacizumab and ranibuzumab have thus been developed to inhibit vascular endothelial growth factor (VEFG)-promoted angiogenesis. While these anti-angiogenic drugs have been commonly used in the treatment of cancer, patients often develop significant resistance that limits the efficacy of anti-VEGF therapies to a short period of time. This is in part due to the fact that an independent pathway of angiogenesis exists, which is mediated by 2-(ω-carboxyethyl)pyrrole (CEP) in a TLR2 receptor-dependent manner that can compensate for inhibition of the VEGF-mediated pathway.


OBJECTIVE
In this work, we evaluated a CEP antibody as a new tumor growth inhibitor that blocks CEP-induced angiogenesis.


METHODS
We first evaluated the effectiveness of a CEP antibody as a monotherapy to impede tumor growth in two human tumor xenograft models. We then determined the synergistic effects of bevacizumab and CEP antibody in a combination therapy, which demonstrated that blocking of the CEP-mediated pathway significantly enhanced the anti-angiogenic efficacy of bevacizumab in tumor growth inhibition indicating that CEP antibody is a promising chemotherapeutic drug. To facilitate potential translational studies of CEP-antibody, we also conducted longitudinal imaging studies and identified that FMISO-PET is a non-invasive imaging tool that can be used to quantitatively monitor the anti-angiogenic effects of CEP-antibody in the clinical setting.


RESULTS
That treatment with CEP antibody induces hypoxia in tumor tissue WHICH was indicated by 43% higher uptake of [18F]FMISO in CEP antibody-treated tumor xenografs than in the control PBS-treated littermates.
Department of Radiology, Case Western Reserve University, 11100 Euclid Ave, Cleveland, OH 44106, United States.
Chunying
C
Wu
Imaging Center, Weifang Medical University, Weifang, Shandong, 261031, China.
Xizhen
X
Wang
Department of Chemistry, Case Western Reserve University, 11100 Euclid Ave, Cleveland, OH 44106, United States.
Nicholas
N
Tomko
Department of Radiology, Case Western Reserve University, 11100 Euclid Ave, Cleveland, OH 44106, United States.
Junqing
J
Zhu
Phillips Academy at Andover, 180 Main Street, Andover, MA 01810, United States.
William R
WR
Wang
Beachwood High School, Beachwood, OH 44122, United States.
Jinle
J
Zhu
Department of Radiology, Bingzhou Medical University, Binzhou, Shandong, 256603, China.
Bin
B
Wangf
Department of Radiology, Case Western Reserve University, 11100 Euclid Ave, Cleveland, OH 44106, United States.
Yanming
Y
Wang
Chemistry, Case Western Reserve University, 11100 Euclid Ave, Cleveland, OH 44106, United States.
Robert G
RG
Salomon
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D011758:Pyrroles / Q000276:immunology*; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
C000602461:2-(omega-carboxyethyl)pyrrole; D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A
2-(ω-carboxyethyl)pyrrole (CEP); Angiogenesis inhibitors; and imaging; bevacizumab; positron
emission tomography (PET); vascular endothelial growth factor (VEGF)
J Mol Med (Berl). 2013 Jun;91(6):749-58
23361368
Chem Res Toxicol. 2014 Dec 15;27(12):2015-22
25380349
Int J Radiat Oncol Biol Phys. 1995 Sep 30;33(2):391-8
7673026
Cancer Cell. 2005 Oct;8(4):269-71
16226701
Nature. 2011 May 19;473(7347):298-307
21593862
Ups J Med Sci. 2012 May;117(2):178-86
22348394
Nature. 2010 Oct 21;467(7318):972-6
20927103
N Engl J Med. 2014 Feb 20;370(8):699-708
24552317
J Cancer. 2014 Aug 15;5(8):633-45
25157274
Int J Oncol. 2012 Nov;41(5):1593-600
22965141
Clin Ther. 2006 Nov;28(11):1779-802
17212999
Mol Oncol. 2015 Jan;9(1):167-78
25224594
Cancer Sci. 2011 Nov;102(11):1949-57
21812860
Nat Rev Cancer. 2010 Jul;10(7):505-14
20574450
J Nucl Med. 2006 Mar;47(3):410-8
16513609
Radiol Clin North Am. 2005 Jan;43(1):169-87
15693655
Cancer Cell. 2007 Jan;11(1):83-95
17222792
PLoS One. 2013;8(2):e56505
23457577
Anticancer Drugs. 2008 Jun;19(5):547-52
18418222
Lab Invest. 2010 Apr;90(4):566-76
20142801
Nat Clin Pract Oncol. 2006 Jan;3(1):24-40
16407877
PLoS One. 2013 Oct 15;8(10):e77117
24143206
J Nucl Med. 2011 Mar;52(3):437-44
21321262
J Clin Oncol. 2010 Jan 20;28(3):453-9
20008624
Cancer Cell. 2005 Oct;8(4):299-309
16226705
Oncotarget. 2014 Jul 15;5(13):4709-21
25015210
N Engl J Med. 1971 Nov 18;285(21):1182-6
4938153
Nature. 2005 Dec 15;438(7070):967-74
16355214
PLoS One. 2013 Oct 01;8(10):e76325
24098476
J Clin Oncol. 2009 Jun 20;27(18):3020-6
19470921
Circ Res. 2004 Mar 19;94(5):664-70
14739162
J Clin Oncol. 2008 Apr 20;26(12):2013-9
18421054
Neuro Oncol. 2010 Jun;12(6):603-7
20156808