Initial testing of the VEGFR inhibitor AZD2171 by the Pediatric Preclinical Testing Program

John M. Maris, Joshua Courtright, Peter J. Houghton, Christopher L. Morton, Richard Gorlick, E. Anders Kolb, Richard Lock, Mayamin Tajbakhsh, C. Patrick Reynolds, Stephen T. Keir, Jianrong Wu, Malcolm A. Smith

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

Background. Inhibition of vascular endothelial growth factor mediated signaling shows promise as an antiangiogenic strategy for solid tumors. AZD2171 is a potent and relatively selective inhibitor of the vascular endothelial growth factor (VEGF) receptor family that is orally bioavailable. This study was designed to screen for antitumor activity of AZD2171 against the in vitro and in vivo childhood cancer preclinical models of the Pediatric Preclinical Testing Program (PPTP). Procedures. AZD2171 was tested at concentrations from 0.1 nM to 1.0 μM against the in vitro panel and was tested against the in vivo tumor panels using a 6-week exposure to daily gavage administration of AZD2171 (3 or 6 mg/kg) or vehicle. Results. One of 22 cell lines evaluated was sensitive to AZD2171 in vitro (maximum concentration 1 μM). Evidence of in vivo antitumor activity (primarily tumor growth delay) was observed in 78% of solid tumor xenografts (3/3 rhabdoid, 2/3 Wilms', 3/3 Ewing's, 5/5 rhabdomyosarcoma, 1/3 medulloblastoma, 2/4 glioblastoma, 5/6 neuroblastoma, 4/5 osteosarcoma). Objective responses (both complete responses) were observed in two of 32 (6%) solid tumor xenografts (a rhabdoid xenograft and an osteosarcoma xenograft). No activity was observed against 7 acute lymphoblastic leukemia models. Conclusions. AZD2171 demonstrated broad tumor growth inhibition against the PPTP's solid tumor xenografts and much less commonly induced tumor regression. This pattern of in vivo activity, combined with the disassociation of in vitro and in vivo efficacy, are consistent with AZD2171 inhibiting growth of the PPTP's solid tumor xenografts primarily through an anti-angiogenesis mechanism of action.

Original languageEnglish (US)
Pages (from-to)581-587
Number of pages7
JournalPediatric Blood and Cancer
Volume50
Issue number3
DOIs
StatePublished - Mar 2008

Fingerprint

Pediatrics
Heterografts
Neoplasms
Osteosarcoma
Growth
cediranib
Vascular Endothelial Growth Factor Receptor
Medulloblastoma
Glioblastoma
Neuroblastoma
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Vascular Endothelial Growth Factor A
Cell Line
In Vitro Techniques

Keywords

  • AZD2171
  • Developmental therapeutics
  • Preclinical testing

ASJC Scopus subject areas

  • Cancer Research
  • Pediatrics, Perinatology, and Child Health
  • Hematology

Cite this

Maris, J. M., Courtright, J., Houghton, P. J., Morton, C. L., Gorlick, R., Kolb, E. A., ... Smith, M. A. (2008). Initial testing of the VEGFR inhibitor AZD2171 by the Pediatric Preclinical Testing Program. Pediatric Blood and Cancer, 50(3), 581-587. https://doi.org/10.1002/pbc.21232

Initial testing of the VEGFR inhibitor AZD2171 by the Pediatric Preclinical Testing Program. / Maris, John M.; Courtright, Joshua; Houghton, Peter J.; Morton, Christopher L.; Gorlick, Richard; Kolb, E. Anders; Lock, Richard; Tajbakhsh, Mayamin; Reynolds, C. Patrick; Keir, Stephen T.; Wu, Jianrong; Smith, Malcolm A.

In: Pediatric Blood and Cancer, Vol. 50, No. 3, 03.2008, p. 581-587.

Research output: Contribution to journalArticle

Maris, JM, Courtright, J, Houghton, PJ, Morton, CL, Gorlick, R, Kolb, EA, Lock, R, Tajbakhsh, M, Reynolds, CP, Keir, ST, Wu, J & Smith, MA 2008, 'Initial testing of the VEGFR inhibitor AZD2171 by the Pediatric Preclinical Testing Program', Pediatric Blood and Cancer, vol. 50, no. 3, pp. 581-587. https://doi.org/10.1002/pbc.21232
Maris JM, Courtright J, Houghton PJ, Morton CL, Gorlick R, Kolb EA et al. Initial testing of the VEGFR inhibitor AZD2171 by the Pediatric Preclinical Testing Program. Pediatric Blood and Cancer. 2008 Mar;50(3):581-587. https://doi.org/10.1002/pbc.21232
Maris, John M. ; Courtright, Joshua ; Houghton, Peter J. ; Morton, Christopher L. ; Gorlick, Richard ; Kolb, E. Anders ; Lock, Richard ; Tajbakhsh, Mayamin ; Reynolds, C. Patrick ; Keir, Stephen T. ; Wu, Jianrong ; Smith, Malcolm A. / Initial testing of the VEGFR inhibitor AZD2171 by the Pediatric Preclinical Testing Program. In: Pediatric Blood and Cancer. 2008 ; Vol. 50, No. 3. pp. 581-587.
@article{7478f3e11f284b26b4d0ce3a73d836e7,
title = "Initial testing of the VEGFR inhibitor AZD2171 by the Pediatric Preclinical Testing Program",
abstract = "Background. Inhibition of vascular endothelial growth factor mediated signaling shows promise as an antiangiogenic strategy for solid tumors. AZD2171 is a potent and relatively selective inhibitor of the vascular endothelial growth factor (VEGF) receptor family that is orally bioavailable. This study was designed to screen for antitumor activity of AZD2171 against the in vitro and in vivo childhood cancer preclinical models of the Pediatric Preclinical Testing Program (PPTP). Procedures. AZD2171 was tested at concentrations from 0.1 nM to 1.0 μM against the in vitro panel and was tested against the in vivo tumor panels using a 6-week exposure to daily gavage administration of AZD2171 (3 or 6 mg/kg) or vehicle. Results. One of 22 cell lines evaluated was sensitive to AZD2171 in vitro (maximum concentration 1 μM). Evidence of in vivo antitumor activity (primarily tumor growth delay) was observed in 78{\%} of solid tumor xenografts (3/3 rhabdoid, 2/3 Wilms', 3/3 Ewing's, 5/5 rhabdomyosarcoma, 1/3 medulloblastoma, 2/4 glioblastoma, 5/6 neuroblastoma, 4/5 osteosarcoma). Objective responses (both complete responses) were observed in two of 32 (6{\%}) solid tumor xenografts (a rhabdoid xenograft and an osteosarcoma xenograft). No activity was observed against 7 acute lymphoblastic leukemia models. Conclusions. AZD2171 demonstrated broad tumor growth inhibition against the PPTP's solid tumor xenografts and much less commonly induced tumor regression. This pattern of in vivo activity, combined with the disassociation of in vitro and in vivo efficacy, are consistent with AZD2171 inhibiting growth of the PPTP's solid tumor xenografts primarily through an anti-angiogenesis mechanism of action.",
keywords = "AZD2171, Developmental therapeutics, Preclinical testing",
author = "Maris, {John M.} and Joshua Courtright and Houghton, {Peter J.} and Morton, {Christopher L.} and Richard Gorlick and Kolb, {E. Anders} and Richard Lock and Mayamin Tajbakhsh and Reynolds, {C. Patrick} and Keir, {Stephen T.} and Jianrong Wu and Smith, {Malcolm A.}",
year = "2008",
month = "3",
doi = "10.1002/pbc.21232",
language = "English (US)",
volume = "50",
pages = "581--587",
journal = "Pediatric Blood and Cancer",
issn = "1545-5009",
publisher = "Wiley-Liss Inc.",
number = "3",

}

TY - JOUR

T1 - Initial testing of the VEGFR inhibitor AZD2171 by the Pediatric Preclinical Testing Program

AU - Maris, John M.

AU - Courtright, Joshua

AU - Houghton, Peter J.

AU - Morton, Christopher L.

AU - Gorlick, Richard

AU - Kolb, E. Anders

AU - Lock, Richard

AU - Tajbakhsh, Mayamin

AU - Reynolds, C. Patrick

AU - Keir, Stephen T.

AU - Wu, Jianrong

AU - Smith, Malcolm A.

PY - 2008/3

Y1 - 2008/3

N2 - Background. Inhibition of vascular endothelial growth factor mediated signaling shows promise as an antiangiogenic strategy for solid tumors. AZD2171 is a potent and relatively selective inhibitor of the vascular endothelial growth factor (VEGF) receptor family that is orally bioavailable. This study was designed to screen for antitumor activity of AZD2171 against the in vitro and in vivo childhood cancer preclinical models of the Pediatric Preclinical Testing Program (PPTP). Procedures. AZD2171 was tested at concentrations from 0.1 nM to 1.0 μM against the in vitro panel and was tested against the in vivo tumor panels using a 6-week exposure to daily gavage administration of AZD2171 (3 or 6 mg/kg) or vehicle. Results. One of 22 cell lines evaluated was sensitive to AZD2171 in vitro (maximum concentration 1 μM). Evidence of in vivo antitumor activity (primarily tumor growth delay) was observed in 78% of solid tumor xenografts (3/3 rhabdoid, 2/3 Wilms', 3/3 Ewing's, 5/5 rhabdomyosarcoma, 1/3 medulloblastoma, 2/4 glioblastoma, 5/6 neuroblastoma, 4/5 osteosarcoma). Objective responses (both complete responses) were observed in two of 32 (6%) solid tumor xenografts (a rhabdoid xenograft and an osteosarcoma xenograft). No activity was observed against 7 acute lymphoblastic leukemia models. Conclusions. AZD2171 demonstrated broad tumor growth inhibition against the PPTP's solid tumor xenografts and much less commonly induced tumor regression. This pattern of in vivo activity, combined with the disassociation of in vitro and in vivo efficacy, are consistent with AZD2171 inhibiting growth of the PPTP's solid tumor xenografts primarily through an anti-angiogenesis mechanism of action.

AB - Background. Inhibition of vascular endothelial growth factor mediated signaling shows promise as an antiangiogenic strategy for solid tumors. AZD2171 is a potent and relatively selective inhibitor of the vascular endothelial growth factor (VEGF) receptor family that is orally bioavailable. This study was designed to screen for antitumor activity of AZD2171 against the in vitro and in vivo childhood cancer preclinical models of the Pediatric Preclinical Testing Program (PPTP). Procedures. AZD2171 was tested at concentrations from 0.1 nM to 1.0 μM against the in vitro panel and was tested against the in vivo tumor panels using a 6-week exposure to daily gavage administration of AZD2171 (3 or 6 mg/kg) or vehicle. Results. One of 22 cell lines evaluated was sensitive to AZD2171 in vitro (maximum concentration 1 μM). Evidence of in vivo antitumor activity (primarily tumor growth delay) was observed in 78% of solid tumor xenografts (3/3 rhabdoid, 2/3 Wilms', 3/3 Ewing's, 5/5 rhabdomyosarcoma, 1/3 medulloblastoma, 2/4 glioblastoma, 5/6 neuroblastoma, 4/5 osteosarcoma). Objective responses (both complete responses) were observed in two of 32 (6%) solid tumor xenografts (a rhabdoid xenograft and an osteosarcoma xenograft). No activity was observed against 7 acute lymphoblastic leukemia models. Conclusions. AZD2171 demonstrated broad tumor growth inhibition against the PPTP's solid tumor xenografts and much less commonly induced tumor regression. This pattern of in vivo activity, combined with the disassociation of in vitro and in vivo efficacy, are consistent with AZD2171 inhibiting growth of the PPTP's solid tumor xenografts primarily through an anti-angiogenesis mechanism of action.

KW - AZD2171

KW - Developmental therapeutics

KW - Preclinical testing

UR - http://www.scopus.com/inward/record.url?scp=38549164180&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=38549164180&partnerID=8YFLogxK

U2 - 10.1002/pbc.21232

DO - 10.1002/pbc.21232

M3 - Article

C2 - 17457854

AN - SCOPUS:38549164180

VL - 50

SP - 581

EP - 587

JO - Pediatric Blood and Cancer

JF - Pediatric Blood and Cancer

SN - 1545-5009

IS - 3

ER -