AZD2171, a Pan-VEGF Receptor Tyrosine Kinase Inhibitor, Normalizes Tumor Vasculature and Alleviates Edema in Glioblastoma Patients

Tracy T. Batchelor; A. Gregory Sorensen; Emmanuelle di Tomaso; Wei Ting Zhang; Dan G G. Duda; Kenneth S. Cohen; Kevin R. Kozak; Daniel P. Cahill; Poe Jou Chen; Mingwang Zhu; Marek Ancukiewicz; Maciej M. Mrugala; Scott Plotkin; Jan Drappatz; David N. Louis; Percy Ivy; David T T. Scadden; Thomas Benner; Jay S. Loeffler; Patrick Y. Wen; Rakesh K. Jain

doi:10.1016/j.ccr.2006.11.021

AZD2171, a Pan-VEGF Receptor Tyrosine Kinase Inhibitor, Normalizes Tumor Vasculature and Alleviates Edema in Glioblastoma Patients

Tracy T. Batchelor, A. Gregory Sorensen, Emmanuelle di Tomaso, Wei Ting Zhang, Dan G G. Duda, Kenneth S. Cohen, Kevin R. Kozak, Daniel P. Cahill, Poe Jou Chen, Mingwang Zhu, Marek Ancukiewicz, Maciej M. Mrugala, Scott Plotkin, Jan Drappatz, David N. Louis, Percy Ivy, David T T. Scadden, Thomas Benner, Jay S. Loeffler, Patrick Y. WenRakesh K. Jain

Neurology

Research output: Contribution to journal › Article › peer-review

1439 Scopus citations

Abstract

Using MRI techniques, we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171-an oral tyrosine kinase inhibitor of VEGF receptors-has rapid onset, is prolonged but reversible, and has the significant clinical benefit of alleviating edema. Reversal of normalization began by 28 days, though some features persisted for as long as four months. Basic FGF, SDF1α, and viable circulating endothelial cells (CECs) increased when tumors escaped treatment, and circulating progenitor cells (CPCs) increased when tumors progressed after drug interruption. Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor.

Original language	English (US)
Pages (from-to)	83-95
Number of pages	13
Journal	Cancer cell
Volume	11
Issue number	1
DOIs	https://doi.org/10.1016/j.ccr.2006.11.021
State	Published - Jan 2007

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccr.2006.11.021

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Batchelor, T. T., Sorensen, A. G., di Tomaso, E., Zhang, W. T., Duda, DG. G., Cohen, K. S., Kozak, K. R., Cahill, D. P., Chen, P. J., Zhu, M., Ancukiewicz, M., Mrugala, M. M., Plotkin, S., Drappatz, J., Louis, D. N., Ivy, P., Scadden, DT. T., Benner, T., Loeffler, J. S., ... Jain, R. K. (2007). AZD2171, a Pan-VEGF Receptor Tyrosine Kinase Inhibitor, Normalizes Tumor Vasculature and Alleviates Edema in Glioblastoma Patients. Cancer cell, 11(1), 83-95. https://doi.org/10.1016/j.ccr.2006.11.021

Batchelor, TT, Sorensen, AG, di Tomaso, E, Zhang, WT, Duda, DGG, Cohen, KS, Kozak, KR, Cahill, DP, Chen, PJ, Zhu, M, Ancukiewicz, M, Mrugala, MM, Plotkin, S, Drappatz, J, Louis, DN, Ivy, P, Scadden, DTT, Benner, T, Loeffler, JS, Wen, PY & Jain, RK 2007, 'AZD2171, a Pan-VEGF Receptor Tyrosine Kinase Inhibitor, Normalizes Tumor Vasculature and Alleviates Edema in Glioblastoma Patients', Cancer cell, vol. 11, no. 1, pp. 83-95. https://doi.org/10.1016/j.ccr.2006.11.021

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title = "AZD2171, a Pan-VEGF Receptor Tyrosine Kinase Inhibitor, Normalizes Tumor Vasculature and Alleviates Edema in Glioblastoma Patients",

abstract = "Using MRI techniques, we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171-an oral tyrosine kinase inhibitor of VEGF receptors-has rapid onset, is prolonged but reversible, and has the significant clinical benefit of alleviating edema. Reversal of normalization began by 28 days, though some features persisted for as long as four months. Basic FGF, SDF1α, and viable circulating endothelial cells (CECs) increased when tumors escaped treatment, and circulating progenitor cells (CPCs) increased when tumors progressed after drug interruption. Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor.",

author = "Batchelor, {Tracy T.} and Sorensen, {A. Gregory} and {di Tomaso}, Emmanuelle and Zhang, {Wei Ting} and Duda, {Dan G G.} and Cohen, {Kenneth S.} and Kozak, {Kevin R.} and Cahill, {Daniel P.} and Chen, {Poe Jou} and Mingwang Zhu and Marek Ancukiewicz and Mrugala, {Maciej M.} and Scott Plotkin and Jan Drappatz and Louis, {David N.} and Percy Ivy and Scadden, {David T T.} and Thomas Benner and Loeffler, {Jay S.} and Wen, {Patrick Y.} and Jain, {Rakesh K.}",

note = "Funding Information: The authors thank H. Chen for thoughtful comments and suggestions on this manuscript; R. Tong for his help in the planning of this trial; K. David, L. Doherty, M. Foley, D. Gigas, R. Klein, J. Kracher, A. Lee, A. Newcomer, L. Ostrowsky, S. Roberge, C. Smith, P. Yeo, and J. Zimmerman for technical support; W. Copen, A. Guimaraes, A. Singhal, O. Wu, and R. Wang for assistance with image acquisition and analysis. This work was supported by an NIH Grant (R21CA117079 to T.T.B.); partial support was obtained from: NIH grants P41-RR14075, M01-RR-01066, P01CA80124, R01CA115767, and R01CA57683; the Richard and Nancy Simches Endowment for Brain Tumor Research; the Montesi Family Fund; MIND Institute; and an AACR-Genentech BioOncology Career Development Award. R.K.J. is a consultant and grantee of AstraZeneca Pharmaceuticals and has received honoraria for presentations at Roche and Pfizer-sponsored symposia. ",

year = "2007",

month = jan,

doi = "10.1016/j.ccr.2006.11.021",

language = "English (US)",

volume = "11",

pages = "83--95",

journal = "Cancer cell",

issn = "1535-6108",

publisher = "Cell Press",

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T1 - AZD2171, a Pan-VEGF Receptor Tyrosine Kinase Inhibitor, Normalizes Tumor Vasculature and Alleviates Edema in Glioblastoma Patients

AU - Batchelor, Tracy T.

AU - Sorensen, A. Gregory

AU - di Tomaso, Emmanuelle

AU - Zhang, Wei Ting

AU - Duda, Dan G G.

AU - Cohen, Kenneth S.

AU - Kozak, Kevin R.

AU - Cahill, Daniel P.

AU - Chen, Poe Jou

AU - Zhu, Mingwang

AU - Ancukiewicz, Marek

AU - Mrugala, Maciej M.

AU - Plotkin, Scott

AU - Drappatz, Jan

AU - Louis, David N.

AU - Ivy, Percy

AU - Scadden, David T T.

AU - Benner, Thomas

AU - Loeffler, Jay S.

AU - Wen, Patrick Y.

AU - Jain, Rakesh K.

N1 - Funding Information: The authors thank H. Chen for thoughtful comments and suggestions on this manuscript; R. Tong for his help in the planning of this trial; K. David, L. Doherty, M. Foley, D. Gigas, R. Klein, J. Kracher, A. Lee, A. Newcomer, L. Ostrowsky, S. Roberge, C. Smith, P. Yeo, and J. Zimmerman for technical support; W. Copen, A. Guimaraes, A. Singhal, O. Wu, and R. Wang for assistance with image acquisition and analysis. This work was supported by an NIH Grant (R21CA117079 to T.T.B.); partial support was obtained from: NIH grants P41-RR14075, M01-RR-01066, P01CA80124, R01CA115767, and R01CA57683; the Richard and Nancy Simches Endowment for Brain Tumor Research; the Montesi Family Fund; MIND Institute; and an AACR-Genentech BioOncology Career Development Award. R.K.J. is a consultant and grantee of AstraZeneca Pharmaceuticals and has received honoraria for presentations at Roche and Pfizer-sponsored symposia.

PY - 2007/1

Y1 - 2007/1

N2 - Using MRI techniques, we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171-an oral tyrosine kinase inhibitor of VEGF receptors-has rapid onset, is prolonged but reversible, and has the significant clinical benefit of alleviating edema. Reversal of normalization began by 28 days, though some features persisted for as long as four months. Basic FGF, SDF1α, and viable circulating endothelial cells (CECs) increased when tumors escaped treatment, and circulating progenitor cells (CPCs) increased when tumors progressed after drug interruption. Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor.

AB - Using MRI techniques, we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171-an oral tyrosine kinase inhibitor of VEGF receptors-has rapid onset, is prolonged but reversible, and has the significant clinical benefit of alleviating edema. Reversal of normalization began by 28 days, though some features persisted for as long as four months. Basic FGF, SDF1α, and viable circulating endothelial cells (CECs) increased when tumors escaped treatment, and circulating progenitor cells (CPCs) increased when tumors progressed after drug interruption. Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor.

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AN - SCOPUS:33846149645

SN - 1535-6108

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JO - Cancer cell

JF - Cancer cell

IS - 1

ER -

AZD2171, a Pan-VEGF Receptor Tyrosine Kinase Inhibitor, Normalizes Tumor Vasculature and Alleviates Edema in Glioblastoma Patients

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