Imaging biomarkers to monitor response to the hypoxia-activated prodrug TH-302 in the MiaPaCa2 flank xenograft model

Julio Cárdenas-Rodríguez; Yuguo Li; Jean Philippe Galons; Heather Cornnell; Robert J. Gillies; Mark D. Pagel; Amanda F. Baker

doi:10.1016/j.mri.2012.02.015

Imaging biomarkers to monitor response to the hypoxia-activated prodrug TH-302 in the MiaPaCa2 flank xenograft model

Julio Cárdenas-Rodríguez, Yuguo Li, Jean Philippe Galons, Heather Cornnell, Robert J. Gillies, Mark D. Pagel, Amanda F. Baker

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

18 Scopus citations

Abstract

TH-302, a hypoxia-activated anticancer prodrug, was evaluated for antitumor activity and changes in dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance imaging (MRI) in a mouse model of pancreatic cancer. TH-302 monotherapy resulted in a significant delay in tumor growth compared to vehicle-treated controls. TH-302 treatment was also associated with a significant decrease in the volume transfer constant (K^trans) compared to vehicle-treated controls 1 day following the first dose measured using DCE-MRI. This early decrease in K^trans following the first dose as measured is consistent with selective killing of the hypoxic fraction of cells which are associated with enhanced expression of hypoxia inducible transcription factor-1 alpha that regulates expression of permeability and perfusion factors including vascular endothelial growth factor-A. No changes were observed in DW-MRI following treatment with TH-302, which may indicate that this technique is not sensitive enough to detect changes in small hypoxic fractions of the tumor targeted by TH-302. These results suggest that changes in tumor permeability and/or perfusion may be an early imaging biomarker for response to TH-302 therapy.

Original language	English (US)
Pages (from-to)	1002-1009
Number of pages	8
Journal	Magnetic Resonance Imaging
Volume	30
Issue number	7
DOIs	https://doi.org/10.1016/j.mri.2012.02.015
State	Published - Sep 2012
Externally published	Yes

Keywords

Diffusion-weighted MRI
Dynamic contrast-enhanced MRI
TH-302
Tumor hypoxia

ASJC Scopus subject areas

Biophysics
Biomedical Engineering
Radiology Nuclear Medicine and imaging

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10.1016/j.mri.2012.02.015

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@article{49b2cee9ae984802bb80cbbd26007e1d,

title = "Imaging biomarkers to monitor response to the hypoxia-activated prodrug TH-302 in the MiaPaCa2 flank xenograft model",

abstract = "TH-302, a hypoxia-activated anticancer prodrug, was evaluated for antitumor activity and changes in dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance imaging (MRI) in a mouse model of pancreatic cancer. TH-302 monotherapy resulted in a significant delay in tumor growth compared to vehicle-treated controls. TH-302 treatment was also associated with a significant decrease in the volume transfer constant (Ktrans) compared to vehicle-treated controls 1 day following the first dose measured using DCE-MRI. This early decrease in Ktrans following the first dose as measured is consistent with selective killing of the hypoxic fraction of cells which are associated with enhanced expression of hypoxia inducible transcription factor-1 alpha that regulates expression of permeability and perfusion factors including vascular endothelial growth factor-A. No changes were observed in DW-MRI following treatment with TH-302, which may indicate that this technique is not sensitive enough to detect changes in small hypoxic fractions of the tumor targeted by TH-302. These results suggest that changes in tumor permeability and/or perfusion may be an early imaging biomarker for response to TH-302 therapy.",

keywords = "Diffusion-weighted MRI, Dynamic contrast-enhanced MRI, TH-302, Tumor hypoxia",

author = "Julio C{\'a}rdenas-Rodr{\'i}guez and Yuguo Li and Galons, {Jean Philippe} and Heather Cornnell and Gillies, {Robert J.} and Pagel, {Mark D.} and Baker, {Amanda F.}",

note = "Funding Information: This work was supported by the Arizona Cancer Center and the National Cancer Institute under grants P50 CA95060 , PO1 CA017094 , R01 CA125627 and P30 CA023074 . J.C.R. is supported through the US Army Medical Research and Materiel Command under grant number W81XWH-09-1-0053 . The authors would like to thank Ms. Christy Howison and the Arizona Cancer Center Experimental Mouse Shared Service for assistance with animal handling, the Arizona Cancer Center, TACMASS and Biometry Shared Services and Ms. Michelle Benson for assistance with data analysis. We would also like to thank Dr. Charles Hart from Threshold Pharmaceuticals for providing TH-302 and for his intellectual contribution and review of this manuscript. Finally, we thank the late Dr. John Curd for his support and guidance.",

year = "2012",

month = sep,

doi = "10.1016/j.mri.2012.02.015",

language = "English (US)",

volume = "30",

pages = "1002--1009",

journal = "Magnetic Resonance Imaging",

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TY - JOUR

T1 - Imaging biomarkers to monitor response to the hypoxia-activated prodrug TH-302 in the MiaPaCa2 flank xenograft model

AU - Cárdenas-Rodríguez, Julio

AU - Li, Yuguo

AU - Galons, Jean Philippe

AU - Cornnell, Heather

AU - Gillies, Robert J.

AU - Pagel, Mark D.

AU - Baker, Amanda F.

N1 - Funding Information: This work was supported by the Arizona Cancer Center and the National Cancer Institute under grants P50 CA95060 , PO1 CA017094 , R01 CA125627 and P30 CA023074 . J.C.R. is supported through the US Army Medical Research and Materiel Command under grant number W81XWH-09-1-0053 . The authors would like to thank Ms. Christy Howison and the Arizona Cancer Center Experimental Mouse Shared Service for assistance with animal handling, the Arizona Cancer Center, TACMASS and Biometry Shared Services and Ms. Michelle Benson for assistance with data analysis. We would also like to thank Dr. Charles Hart from Threshold Pharmaceuticals for providing TH-302 and for his intellectual contribution and review of this manuscript. Finally, we thank the late Dr. John Curd for his support and guidance.

PY - 2012/9

Y1 - 2012/9

N2 - TH-302, a hypoxia-activated anticancer prodrug, was evaluated for antitumor activity and changes in dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance imaging (MRI) in a mouse model of pancreatic cancer. TH-302 monotherapy resulted in a significant delay in tumor growth compared to vehicle-treated controls. TH-302 treatment was also associated with a significant decrease in the volume transfer constant (Ktrans) compared to vehicle-treated controls 1 day following the first dose measured using DCE-MRI. This early decrease in Ktrans following the first dose as measured is consistent with selective killing of the hypoxic fraction of cells which are associated with enhanced expression of hypoxia inducible transcription factor-1 alpha that regulates expression of permeability and perfusion factors including vascular endothelial growth factor-A. No changes were observed in DW-MRI following treatment with TH-302, which may indicate that this technique is not sensitive enough to detect changes in small hypoxic fractions of the tumor targeted by TH-302. These results suggest that changes in tumor permeability and/or perfusion may be an early imaging biomarker for response to TH-302 therapy.

AB - TH-302, a hypoxia-activated anticancer prodrug, was evaluated for antitumor activity and changes in dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance imaging (MRI) in a mouse model of pancreatic cancer. TH-302 monotherapy resulted in a significant delay in tumor growth compared to vehicle-treated controls. TH-302 treatment was also associated with a significant decrease in the volume transfer constant (Ktrans) compared to vehicle-treated controls 1 day following the first dose measured using DCE-MRI. This early decrease in Ktrans following the first dose as measured is consistent with selective killing of the hypoxic fraction of cells which are associated with enhanced expression of hypoxia inducible transcription factor-1 alpha that regulates expression of permeability and perfusion factors including vascular endothelial growth factor-A. No changes were observed in DW-MRI following treatment with TH-302, which may indicate that this technique is not sensitive enough to detect changes in small hypoxic fractions of the tumor targeted by TH-302. These results suggest that changes in tumor permeability and/or perfusion may be an early imaging biomarker for response to TH-302 therapy.

KW - Diffusion-weighted MRI

KW - Dynamic contrast-enhanced MRI

KW - TH-302

KW - Tumor hypoxia

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ER -

Imaging biomarkers to monitor response to the hypoxia-activated prodrug TH-302 in the MiaPaCa2 flank xenograft model

Abstract

Keywords

ASJC Scopus subject areas

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