Cargando…

The Adnectin CT-322 is a novel VEGF receptor 2 inhibitor that decreases tumor burden in an orthotopic mouse model of pancreatic cancer

BACKGROUND: Pancreatic cancer continues to have a 5-year survival of less than 5%. Therefore, more effective therapies are necessary to improve prognosis in this disease. Angiogenesis is required for tumor growth, and subsequently, mediators of angiogenesis are attractive targets for therapy. Vascul...

Descripción completa

Detalles Bibliográficos
Autores principales: Dineen, Sean P, Sullivan, Laura A, Beck, Adam W, Miller, Andrew F, Carbon, Juliet G, Mamluk, Roni, Wong, Henry, Brekken, Rolf A
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2627916/
https://www.ncbi.nlm.nih.gov/pubmed/19038046
http://dx.doi.org/10.1186/1471-2407-8-352
_version_ 1782163618944516096
author Dineen, Sean P
Sullivan, Laura A
Beck, Adam W
Miller, Andrew F
Carbon, Juliet G
Mamluk, Roni
Wong, Henry
Brekken, Rolf A
author_facet Dineen, Sean P
Sullivan, Laura A
Beck, Adam W
Miller, Andrew F
Carbon, Juliet G
Mamluk, Roni
Wong, Henry
Brekken, Rolf A
author_sort Dineen, Sean P
collection PubMed
description BACKGROUND: Pancreatic cancer continues to have a 5-year survival of less than 5%. Therefore, more effective therapies are necessary to improve prognosis in this disease. Angiogenesis is required for tumor growth, and subsequently, mediators of angiogenesis are attractive targets for therapy. Vascular endothelial growth factor (VEGF) is a well-characterized mediator of tumor angiogenesis that functions primarily by binding and activating VEGF receptor 2 (VEGFR2). In this study, we evaluate the use of CT-322, a novel biologic (Adnectin). This small protein is based on a human fibronectin domain and has beneficial properties in that it is fully human, stable, and is produced in bacteria. CT-322 binds to and inhibits activation of VEGFR2. METHODS: The efficacy of CT-322 was evaluated in vivo using two orthotopic pancreatic tumor models. The first model was a human tumor xenograft where MiaPaCa-2 cells were injected into the tail of the pancreas of nude mice. The second model was a syngeneic tumor using Pan02 cells injected into pancreas of C57BL/6J mice. In both models, therapy was initiated once primary tumors were established. Mice bearing MiaPaCa-2 tumors were treated with vehicle or CT-322 alone. Gemcitabine alone or in combination with CT-322 was added to the treatment regimen of mice bearing Pan02 tumors. Therapy was given twice a week for six weeks, after which the animals were sacrificed and evaluated (grossly and histologically) for primary and metastatic tumor burden. Primary tumors were also evaluated by immunohistochemistry for the level of apoptosis (TUNEL), microvessel density (MECA-32), and VEGF-activated blood vessels (Gv39M). RESULTS: Treatment with CT-322 was effective at preventing pancreatic tumor growth and metastasis in orthotopic xenograft and syngeneic models of pancreatic cancer. Additionally, CT-322 treatment increased apoptosis, reduced microvessel density and reduced the number of VEGF-activated blood vessels in tumors. Finally, CT-322, in combination with gemcitabine was safe and effective at controlling the growth of syngeneic pancreatic tumors in immunocompetent mice. CONCLUSION: We conclude that CT-322 is an effective anti-VEGFR2 agent and that further investigation of CT-322 for the treatment of pancreatic cancer is warranted.
format Text
id pubmed-2627916
institution National Center for Biotechnology Information
language English
publishDate 2008
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-26279162009-01-17 The Adnectin CT-322 is a novel VEGF receptor 2 inhibitor that decreases tumor burden in an orthotopic mouse model of pancreatic cancer Dineen, Sean P Sullivan, Laura A Beck, Adam W Miller, Andrew F Carbon, Juliet G Mamluk, Roni Wong, Henry Brekken, Rolf A BMC Cancer Research Article BACKGROUND: Pancreatic cancer continues to have a 5-year survival of less than 5%. Therefore, more effective therapies are necessary to improve prognosis in this disease. Angiogenesis is required for tumor growth, and subsequently, mediators of angiogenesis are attractive targets for therapy. Vascular endothelial growth factor (VEGF) is a well-characterized mediator of tumor angiogenesis that functions primarily by binding and activating VEGF receptor 2 (VEGFR2). In this study, we evaluate the use of CT-322, a novel biologic (Adnectin). This small protein is based on a human fibronectin domain and has beneficial properties in that it is fully human, stable, and is produced in bacteria. CT-322 binds to and inhibits activation of VEGFR2. METHODS: The efficacy of CT-322 was evaluated in vivo using two orthotopic pancreatic tumor models. The first model was a human tumor xenograft where MiaPaCa-2 cells were injected into the tail of the pancreas of nude mice. The second model was a syngeneic tumor using Pan02 cells injected into pancreas of C57BL/6J mice. In both models, therapy was initiated once primary tumors were established. Mice bearing MiaPaCa-2 tumors were treated with vehicle or CT-322 alone. Gemcitabine alone or in combination with CT-322 was added to the treatment regimen of mice bearing Pan02 tumors. Therapy was given twice a week for six weeks, after which the animals were sacrificed and evaluated (grossly and histologically) for primary and metastatic tumor burden. Primary tumors were also evaluated by immunohistochemistry for the level of apoptosis (TUNEL), microvessel density (MECA-32), and VEGF-activated blood vessels (Gv39M). RESULTS: Treatment with CT-322 was effective at preventing pancreatic tumor growth and metastasis in orthotopic xenograft and syngeneic models of pancreatic cancer. Additionally, CT-322 treatment increased apoptosis, reduced microvessel density and reduced the number of VEGF-activated blood vessels in tumors. Finally, CT-322, in combination with gemcitabine was safe and effective at controlling the growth of syngeneic pancreatic tumors in immunocompetent mice. CONCLUSION: We conclude that CT-322 is an effective anti-VEGFR2 agent and that further investigation of CT-322 for the treatment of pancreatic cancer is warranted. BioMed Central 2008-11-27 /pmc/articles/PMC2627916/ /pubmed/19038046 http://dx.doi.org/10.1186/1471-2407-8-352 Text en Copyright © 2008 Dineen et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Dineen, Sean P
Sullivan, Laura A
Beck, Adam W
Miller, Andrew F
Carbon, Juliet G
Mamluk, Roni
Wong, Henry
Brekken, Rolf A
The Adnectin CT-322 is a novel VEGF receptor 2 inhibitor that decreases tumor burden in an orthotopic mouse model of pancreatic cancer
title The Adnectin CT-322 is a novel VEGF receptor 2 inhibitor that decreases tumor burden in an orthotopic mouse model of pancreatic cancer
title_full The Adnectin CT-322 is a novel VEGF receptor 2 inhibitor that decreases tumor burden in an orthotopic mouse model of pancreatic cancer
title_fullStr The Adnectin CT-322 is a novel VEGF receptor 2 inhibitor that decreases tumor burden in an orthotopic mouse model of pancreatic cancer
title_full_unstemmed The Adnectin CT-322 is a novel VEGF receptor 2 inhibitor that decreases tumor burden in an orthotopic mouse model of pancreatic cancer
title_short The Adnectin CT-322 is a novel VEGF receptor 2 inhibitor that decreases tumor burden in an orthotopic mouse model of pancreatic cancer
title_sort adnectin ct-322 is a novel vegf receptor 2 inhibitor that decreases tumor burden in an orthotopic mouse model of pancreatic cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2627916/
https://www.ncbi.nlm.nih.gov/pubmed/19038046
http://dx.doi.org/10.1186/1471-2407-8-352
work_keys_str_mv AT dineenseanp theadnectinct322isanovelvegfreceptor2inhibitorthatdecreasestumorburdeninanorthotopicmousemodelofpancreaticcancer
AT sullivanlauraa theadnectinct322isanovelvegfreceptor2inhibitorthatdecreasestumorburdeninanorthotopicmousemodelofpancreaticcancer
AT beckadamw theadnectinct322isanovelvegfreceptor2inhibitorthatdecreasestumorburdeninanorthotopicmousemodelofpancreaticcancer
AT millerandrewf theadnectinct322isanovelvegfreceptor2inhibitorthatdecreasestumorburdeninanorthotopicmousemodelofpancreaticcancer
AT carbonjulietg theadnectinct322isanovelvegfreceptor2inhibitorthatdecreasestumorburdeninanorthotopicmousemodelofpancreaticcancer
AT mamlukroni theadnectinct322isanovelvegfreceptor2inhibitorthatdecreasestumorburdeninanorthotopicmousemodelofpancreaticcancer
AT wonghenry theadnectinct322isanovelvegfreceptor2inhibitorthatdecreasestumorburdeninanorthotopicmousemodelofpancreaticcancer
AT brekkenrolfa theadnectinct322isanovelvegfreceptor2inhibitorthatdecreasestumorburdeninanorthotopicmousemodelofpancreaticcancer
AT dineenseanp adnectinct322isanovelvegfreceptor2inhibitorthatdecreasestumorburdeninanorthotopicmousemodelofpancreaticcancer
AT sullivanlauraa adnectinct322isanovelvegfreceptor2inhibitorthatdecreasestumorburdeninanorthotopicmousemodelofpancreaticcancer
AT beckadamw adnectinct322isanovelvegfreceptor2inhibitorthatdecreasestumorburdeninanorthotopicmousemodelofpancreaticcancer
AT millerandrewf adnectinct322isanovelvegfreceptor2inhibitorthatdecreasestumorburdeninanorthotopicmousemodelofpancreaticcancer
AT carbonjulietg adnectinct322isanovelvegfreceptor2inhibitorthatdecreasestumorburdeninanorthotopicmousemodelofpancreaticcancer
AT mamlukroni adnectinct322isanovelvegfreceptor2inhibitorthatdecreasestumorburdeninanorthotopicmousemodelofpancreaticcancer
AT wonghenry adnectinct322isanovelvegfreceptor2inhibitorthatdecreasestumorburdeninanorthotopicmousemodelofpancreaticcancer
AT brekkenrolfa adnectinct322isanovelvegfreceptor2inhibitorthatdecreasestumorburdeninanorthotopicmousemodelofpancreaticcancer