Differential Efficacy of Combined Therapy With Radiation and AEE788 in High and Low EGFR-Expressing Androgen-Independent Prostate Tumor Models

Jessica Huamani, Christopher Willey, Dinesh Thotala, Kenneth J. Niermann, Michelle Reyzer, Lauren Leavitt, Cameron Jones, Arthur Fleishcher, Richard Caprioli, Dennis E. Hallahan, Dong Wook Nathan Kim

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Purpose: To determine the efficacy of combining radiation (XRT) with a dual epidermal growth factor receptor (EGFR)/vascular endothelial growth factor receptor inhibitor, AEE788, in prostate cancer models with different levels of EGFR expression. Methods and Materials: Immunoblotting was performed for EGFR, phosphorylated-EGFR, and phosphorylated-AKT in prostate cancer cells. Clonogenic assays were performed on DU145, PC-3, and human umbilical vein endothelial cells treated with XRT ± AEE788. Tumor xenografts were established for DU145 and PC-3 on hind limbs of athymic nude mice assigned to four treatment groups: (1) control, (2) AEE788, (3) XRT, and (4) AEE788 + XRT. Tumor blood flow and growth measurements were performed using immunohistochemistry and imaging. Results: AEE788 effectively decreased phosphorylated-EGFR and phosphorylated-AKT levels in DU145 and PC-3 cells. Clonogenic assays showed no radiosensitization for DU145 and PC-3 colonies treated with AEE788 + XRT. However, AEE788 caused decreased proliferation in DU145 cells. AEE788 showed a radiosensitization effect in human umbilical vein endothelial cells and increased apoptosis susceptibility. Concurrent AEE788 + XRT compared with either alone led to significant tumor growth delay in DU145 tumors. Conversely, PC-3 tumors derived no added benefit from combined-modality therapy. In DU145 tumors, a significant decrease in tumor blood flow with combination therapy was shown by using power Doppler sonography and tumor blood vessel destruction on immunohistochemistry. Maldi-spectrometry (MS) imaging showed that AEE788 is bioavailable and heterogeneously distributed in DU145 tumors undergoing therapy. Conclusions: AEE788 + XRT showed efficacy in vitro/in vivo with DU145-based cell models, whereas PC-3-based models were adequately treated with XRT alone without added benefit from combination therapy. These findings correlated with differences in EGFR expression and showed effects on both tumor cell proliferation and vascular destruction.

Original languageEnglish (US)
Pages (from-to)237-246
Number of pages10
JournalInternational Journal of Radiation Oncology Biology Physics
Volume71
Issue number1
DOIs
StatePublished - May 1 2008

Fingerprint

Epidermal Growth Factor Receptor
Androgens
Prostate
therapy
Radiotherapy
tumors
radiation
Neoplasms
blood flow
Human Umbilical Vein Endothelial Cells
veins
destruction
Nude Mice
Prostatic Neoplasms
cancer
cells
AEE 788
Immunohistochemistry
Vascular Tissue Neoplasms
Doppler Ultrasonography

Keywords

  • AEE788
  • EGFR
  • Prostate Cancer
  • Radiation therapy
  • VEGFR

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Radiation

Cite this

Differential Efficacy of Combined Therapy With Radiation and AEE788 in High and Low EGFR-Expressing Androgen-Independent Prostate Tumor Models. / Huamani, Jessica; Willey, Christopher; Thotala, Dinesh; Niermann, Kenneth J.; Reyzer, Michelle; Leavitt, Lauren; Jones, Cameron; Fleishcher, Arthur; Caprioli, Richard; Hallahan, Dennis E.; Kim, Dong Wook Nathan.

In: International Journal of Radiation Oncology Biology Physics, Vol. 71, No. 1, 01.05.2008, p. 237-246.

Research output: Contribution to journalArticle

Huamani, J, Willey, C, Thotala, D, Niermann, KJ, Reyzer, M, Leavitt, L, Jones, C, Fleishcher, A, Caprioli, R, Hallahan, DE & Kim, DWN 2008, 'Differential Efficacy of Combined Therapy With Radiation and AEE788 in High and Low EGFR-Expressing Androgen-Independent Prostate Tumor Models', International Journal of Radiation Oncology Biology Physics, vol. 71, no. 1, pp. 237-246. https://doi.org/10.1016/j.ijrobp.2007.12.049
Huamani, Jessica ; Willey, Christopher ; Thotala, Dinesh ; Niermann, Kenneth J. ; Reyzer, Michelle ; Leavitt, Lauren ; Jones, Cameron ; Fleishcher, Arthur ; Caprioli, Richard ; Hallahan, Dennis E. ; Kim, Dong Wook Nathan. / Differential Efficacy of Combined Therapy With Radiation and AEE788 in High and Low EGFR-Expressing Androgen-Independent Prostate Tumor Models. In: International Journal of Radiation Oncology Biology Physics. 2008 ; Vol. 71, No. 1. pp. 237-246.
@article{7fad49dfe6bf44a3b43b1215ebd7b347,
title = "Differential Efficacy of Combined Therapy With Radiation and AEE788 in High and Low EGFR-Expressing Androgen-Independent Prostate Tumor Models",
abstract = "Purpose: To determine the efficacy of combining radiation (XRT) with a dual epidermal growth factor receptor (EGFR)/vascular endothelial growth factor receptor inhibitor, AEE788, in prostate cancer models with different levels of EGFR expression. Methods and Materials: Immunoblotting was performed for EGFR, phosphorylated-EGFR, and phosphorylated-AKT in prostate cancer cells. Clonogenic assays were performed on DU145, PC-3, and human umbilical vein endothelial cells treated with XRT ± AEE788. Tumor xenografts were established for DU145 and PC-3 on hind limbs of athymic nude mice assigned to four treatment groups: (1) control, (2) AEE788, (3) XRT, and (4) AEE788 + XRT. Tumor blood flow and growth measurements were performed using immunohistochemistry and imaging. Results: AEE788 effectively decreased phosphorylated-EGFR and phosphorylated-AKT levels in DU145 and PC-3 cells. Clonogenic assays showed no radiosensitization for DU145 and PC-3 colonies treated with AEE788 + XRT. However, AEE788 caused decreased proliferation in DU145 cells. AEE788 showed a radiosensitization effect in human umbilical vein endothelial cells and increased apoptosis susceptibility. Concurrent AEE788 + XRT compared with either alone led to significant tumor growth delay in DU145 tumors. Conversely, PC-3 tumors derived no added benefit from combined-modality therapy. In DU145 tumors, a significant decrease in tumor blood flow with combination therapy was shown by using power Doppler sonography and tumor blood vessel destruction on immunohistochemistry. Maldi-spectrometry (MS) imaging showed that AEE788 is bioavailable and heterogeneously distributed in DU145 tumors undergoing therapy. Conclusions: AEE788 + XRT showed efficacy in vitro/in vivo with DU145-based cell models, whereas PC-3-based models were adequately treated with XRT alone without added benefit from combination therapy. These findings correlated with differences in EGFR expression and showed effects on both tumor cell proliferation and vascular destruction.",
keywords = "AEE788, EGFR, Prostate Cancer, Radiation therapy, VEGFR",
author = "Jessica Huamani and Christopher Willey and Dinesh Thotala and Niermann, {Kenneth J.} and Michelle Reyzer and Lauren Leavitt and Cameron Jones and Arthur Fleishcher and Richard Caprioli and Hallahan, {Dennis E.} and Kim, {Dong Wook Nathan}",
year = "2008",
month = "5",
day = "1",
doi = "10.1016/j.ijrobp.2007.12.049",
language = "English (US)",
volume = "71",
pages = "237--246",
journal = "International Journal of Radiation Oncology Biology Physics",
issn = "0360-3016",
publisher = "Elsevier Inc.",
number = "1",

}

TY - JOUR

T1 - Differential Efficacy of Combined Therapy With Radiation and AEE788 in High and Low EGFR-Expressing Androgen-Independent Prostate Tumor Models

AU - Huamani, Jessica

AU - Willey, Christopher

AU - Thotala, Dinesh

AU - Niermann, Kenneth J.

AU - Reyzer, Michelle

AU - Leavitt, Lauren

AU - Jones, Cameron

AU - Fleishcher, Arthur

AU - Caprioli, Richard

AU - Hallahan, Dennis E.

AU - Kim, Dong Wook Nathan

PY - 2008/5/1

Y1 - 2008/5/1

N2 - Purpose: To determine the efficacy of combining radiation (XRT) with a dual epidermal growth factor receptor (EGFR)/vascular endothelial growth factor receptor inhibitor, AEE788, in prostate cancer models with different levels of EGFR expression. Methods and Materials: Immunoblotting was performed for EGFR, phosphorylated-EGFR, and phosphorylated-AKT in prostate cancer cells. Clonogenic assays were performed on DU145, PC-3, and human umbilical vein endothelial cells treated with XRT ± AEE788. Tumor xenografts were established for DU145 and PC-3 on hind limbs of athymic nude mice assigned to four treatment groups: (1) control, (2) AEE788, (3) XRT, and (4) AEE788 + XRT. Tumor blood flow and growth measurements were performed using immunohistochemistry and imaging. Results: AEE788 effectively decreased phosphorylated-EGFR and phosphorylated-AKT levels in DU145 and PC-3 cells. Clonogenic assays showed no radiosensitization for DU145 and PC-3 colonies treated with AEE788 + XRT. However, AEE788 caused decreased proliferation in DU145 cells. AEE788 showed a radiosensitization effect in human umbilical vein endothelial cells and increased apoptosis susceptibility. Concurrent AEE788 + XRT compared with either alone led to significant tumor growth delay in DU145 tumors. Conversely, PC-3 tumors derived no added benefit from combined-modality therapy. In DU145 tumors, a significant decrease in tumor blood flow with combination therapy was shown by using power Doppler sonography and tumor blood vessel destruction on immunohistochemistry. Maldi-spectrometry (MS) imaging showed that AEE788 is bioavailable and heterogeneously distributed in DU145 tumors undergoing therapy. Conclusions: AEE788 + XRT showed efficacy in vitro/in vivo with DU145-based cell models, whereas PC-3-based models were adequately treated with XRT alone without added benefit from combination therapy. These findings correlated with differences in EGFR expression and showed effects on both tumor cell proliferation and vascular destruction.

AB - Purpose: To determine the efficacy of combining radiation (XRT) with a dual epidermal growth factor receptor (EGFR)/vascular endothelial growth factor receptor inhibitor, AEE788, in prostate cancer models with different levels of EGFR expression. Methods and Materials: Immunoblotting was performed for EGFR, phosphorylated-EGFR, and phosphorylated-AKT in prostate cancer cells. Clonogenic assays were performed on DU145, PC-3, and human umbilical vein endothelial cells treated with XRT ± AEE788. Tumor xenografts were established for DU145 and PC-3 on hind limbs of athymic nude mice assigned to four treatment groups: (1) control, (2) AEE788, (3) XRT, and (4) AEE788 + XRT. Tumor blood flow and growth measurements were performed using immunohistochemistry and imaging. Results: AEE788 effectively decreased phosphorylated-EGFR and phosphorylated-AKT levels in DU145 and PC-3 cells. Clonogenic assays showed no radiosensitization for DU145 and PC-3 colonies treated with AEE788 + XRT. However, AEE788 caused decreased proliferation in DU145 cells. AEE788 showed a radiosensitization effect in human umbilical vein endothelial cells and increased apoptosis susceptibility. Concurrent AEE788 + XRT compared with either alone led to significant tumor growth delay in DU145 tumors. Conversely, PC-3 tumors derived no added benefit from combined-modality therapy. In DU145 tumors, a significant decrease in tumor blood flow with combination therapy was shown by using power Doppler sonography and tumor blood vessel destruction on immunohistochemistry. Maldi-spectrometry (MS) imaging showed that AEE788 is bioavailable and heterogeneously distributed in DU145 tumors undergoing therapy. Conclusions: AEE788 + XRT showed efficacy in vitro/in vivo with DU145-based cell models, whereas PC-3-based models were adequately treated with XRT alone without added benefit from combination therapy. These findings correlated with differences in EGFR expression and showed effects on both tumor cell proliferation and vascular destruction.

KW - AEE788

KW - EGFR

KW - Prostate Cancer

KW - Radiation therapy

KW - VEGFR

UR - http://www.scopus.com/inward/record.url?scp=41749123020&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=41749123020&partnerID=8YFLogxK

U2 - 10.1016/j.ijrobp.2007.12.049

DO - 10.1016/j.ijrobp.2007.12.049

M3 - Article

VL - 71

SP - 237

EP - 246

JO - International Journal of Radiation Oncology Biology Physics

JF - International Journal of Radiation Oncology Biology Physics

SN - 0360-3016

IS - 1

ER -