Combining EGFR and mTOR blockade for the treatment of epithelioid sarcoma

Xianbiao Xie, Markus P H Ghadimi, Eric D. Young, Roman Belousov, Quan Sheng Zhu, Juehui Liu, Gonzalo Lopez, Chiara Colombo, Tingsheng Peng, David Reynoso, Jason L. Hornick, Alexander J. Lazar, Dina Lev

Research output: Contribution to journalArticle

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Abstract

Purpose: Molecular deregulations underlying epithelioid sarcoma (ES) progression are poorly understood yet critically needed to develop new therapies. Epidermal growth factor receptor (EGFR) is over-expressed in ES; using preclinical models, we examined the ES EGFR role and assessed anti-ES EGFR blockade effects, alone and with mTOR inhibition. Experimental Design: EGFR and mTOR expression/activation was examined via tissue microarray (n = 27 human ES specimens; immunohistochemistry) and in human ES cell lines (Western blot and quantitative reverse transcriptase PCR). Cell proliferation, survival, migration, and invasion effects of EGFR and mTOR activation treated with erlotinib (anti-EGFR small-molecule inhibitor) alone and combined with rapamycin were assessed in cell culture assays. In vivo growth effects of erlotinib alone or with rapamycin were evaluated using severe combined immunodeficient mouse ES xenograft models. Results: EGFR was expressed and activated in ES specimens and cell lines. EGFR activation increased ES cell proliferation, motility, and invasion and induced cyclin D1, matrix metalloproteinase (MMP) 2, and MMP9 expression. EGFR blockade inhibited these processes and caused significant cytostatic ES growth inhibition in vivo. mTOR pathway activation at varying levels was identified in all tissue microarray-evaluable ES tissues; 88% of samples had no or reduced PTEN expression. Similarly, both ES cell lines showed enhanced mTOR activity; VAESBJ cells exhibited constitutive mTOR activation uncoupled from EGFR signaling. Most importantly, combined erlotinib/rapamycin resulted in synergistic anti-ES effects in vitro and induced superior tumor growth inhibition in vivo versus single agent administration. Conclusions: EGFR and mTOR signaling pathways are deregulated in ES. Preclinical ES model-derived insights suggest that combined inhibition of these targets might be beneficial, supporting evaluations in clinical trials.

Original languageEnglish (US)
Pages (from-to)5901-5912
Number of pages12
JournalClinical Cancer Research
Volume17
Issue number18
DOIs
StatePublished - Sep 15 2011
Externally publishedYes

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Epidermal Growth Factor Receptor
Sarcoma
Epithelioid Cells
Therapeutics
Sirolimus
Cell Line
Growth
Cell Proliferation
SCID Mice
Matrix Metalloproteinase 2
Cyclin D1
Cytostatic Agents
Reverse Transcriptase Polymerase Chain Reaction
Heterografts
Cell Movement
Cell Survival
Research Design
Cell Culture Techniques
Western Blotting
Immunohistochemistry

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Xie, X., Ghadimi, M. P. H., Young, E. D., Belousov, R., Zhu, Q. S., Liu, J., ... Lev, D. (2011). Combining EGFR and mTOR blockade for the treatment of epithelioid sarcoma. Clinical Cancer Research, 17(18), 5901-5912. https://doi.org/10.1158/1078-0432.CCR-11-0660

Combining EGFR and mTOR blockade for the treatment of epithelioid sarcoma. / Xie, Xianbiao; Ghadimi, Markus P H; Young, Eric D.; Belousov, Roman; Zhu, Quan Sheng; Liu, Juehui; Lopez, Gonzalo; Colombo, Chiara; Peng, Tingsheng; Reynoso, David; Hornick, Jason L.; Lazar, Alexander J.; Lev, Dina.

In: Clinical Cancer Research, Vol. 17, No. 18, 15.09.2011, p. 5901-5912.

Research output: Contribution to journalArticle

Xie, X, Ghadimi, MPH, Young, ED, Belousov, R, Zhu, QS, Liu, J, Lopez, G, Colombo, C, Peng, T, Reynoso, D, Hornick, JL, Lazar, AJ & Lev, D 2011, 'Combining EGFR and mTOR blockade for the treatment of epithelioid sarcoma', Clinical Cancer Research, vol. 17, no. 18, pp. 5901-5912. https://doi.org/10.1158/1078-0432.CCR-11-0660
Xie X, Ghadimi MPH, Young ED, Belousov R, Zhu QS, Liu J et al. Combining EGFR and mTOR blockade for the treatment of epithelioid sarcoma. Clinical Cancer Research. 2011 Sep 15;17(18):5901-5912. https://doi.org/10.1158/1078-0432.CCR-11-0660
Xie, Xianbiao ; Ghadimi, Markus P H ; Young, Eric D. ; Belousov, Roman ; Zhu, Quan Sheng ; Liu, Juehui ; Lopez, Gonzalo ; Colombo, Chiara ; Peng, Tingsheng ; Reynoso, David ; Hornick, Jason L. ; Lazar, Alexander J. ; Lev, Dina. / Combining EGFR and mTOR blockade for the treatment of epithelioid sarcoma. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 18. pp. 5901-5912.
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abstract = "Purpose: Molecular deregulations underlying epithelioid sarcoma (ES) progression are poorly understood yet critically needed to develop new therapies. Epidermal growth factor receptor (EGFR) is over-expressed in ES; using preclinical models, we examined the ES EGFR role and assessed anti-ES EGFR blockade effects, alone and with mTOR inhibition. Experimental Design: EGFR and mTOR expression/activation was examined via tissue microarray (n = 27 human ES specimens; immunohistochemistry) and in human ES cell lines (Western blot and quantitative reverse transcriptase PCR). Cell proliferation, survival, migration, and invasion effects of EGFR and mTOR activation treated with erlotinib (anti-EGFR small-molecule inhibitor) alone and combined with rapamycin were assessed in cell culture assays. In vivo growth effects of erlotinib alone or with rapamycin were evaluated using severe combined immunodeficient mouse ES xenograft models. Results: EGFR was expressed and activated in ES specimens and cell lines. EGFR activation increased ES cell proliferation, motility, and invasion and induced cyclin D1, matrix metalloproteinase (MMP) 2, and MMP9 expression. EGFR blockade inhibited these processes and caused significant cytostatic ES growth inhibition in vivo. mTOR pathway activation at varying levels was identified in all tissue microarray-evaluable ES tissues; 88{\%} of samples had no or reduced PTEN expression. Similarly, both ES cell lines showed enhanced mTOR activity; VAESBJ cells exhibited constitutive mTOR activation uncoupled from EGFR signaling. Most importantly, combined erlotinib/rapamycin resulted in synergistic anti-ES effects in vitro and induced superior tumor growth inhibition in vivo versus single agent administration. Conclusions: EGFR and mTOR signaling pathways are deregulated in ES. Preclinical ES model-derived insights suggest that combined inhibition of these targets might be beneficial, supporting evaluations in clinical trials.",
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AU - Xie, Xianbiao

AU - Ghadimi, Markus P H

AU - Young, Eric D.

AU - Belousov, Roman

AU - Zhu, Quan Sheng

AU - Liu, Juehui

AU - Lopez, Gonzalo

AU - Colombo, Chiara

AU - Peng, Tingsheng

AU - Reynoso, David

AU - Hornick, Jason L.

AU - Lazar, Alexander J.

AU - Lev, Dina

PY - 2011/9/15

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N2 - Purpose: Molecular deregulations underlying epithelioid sarcoma (ES) progression are poorly understood yet critically needed to develop new therapies. Epidermal growth factor receptor (EGFR) is over-expressed in ES; using preclinical models, we examined the ES EGFR role and assessed anti-ES EGFR blockade effects, alone and with mTOR inhibition. Experimental Design: EGFR and mTOR expression/activation was examined via tissue microarray (n = 27 human ES specimens; immunohistochemistry) and in human ES cell lines (Western blot and quantitative reverse transcriptase PCR). Cell proliferation, survival, migration, and invasion effects of EGFR and mTOR activation treated with erlotinib (anti-EGFR small-molecule inhibitor) alone and combined with rapamycin were assessed in cell culture assays. In vivo growth effects of erlotinib alone or with rapamycin were evaluated using severe combined immunodeficient mouse ES xenograft models. Results: EGFR was expressed and activated in ES specimens and cell lines. EGFR activation increased ES cell proliferation, motility, and invasion and induced cyclin D1, matrix metalloproteinase (MMP) 2, and MMP9 expression. EGFR blockade inhibited these processes and caused significant cytostatic ES growth inhibition in vivo. mTOR pathway activation at varying levels was identified in all tissue microarray-evaluable ES tissues; 88% of samples had no or reduced PTEN expression. Similarly, both ES cell lines showed enhanced mTOR activity; VAESBJ cells exhibited constitutive mTOR activation uncoupled from EGFR signaling. Most importantly, combined erlotinib/rapamycin resulted in synergistic anti-ES effects in vitro and induced superior tumor growth inhibition in vivo versus single agent administration. Conclusions: EGFR and mTOR signaling pathways are deregulated in ES. Preclinical ES model-derived insights suggest that combined inhibition of these targets might be beneficial, supporting evaluations in clinical trials.

AB - Purpose: Molecular deregulations underlying epithelioid sarcoma (ES) progression are poorly understood yet critically needed to develop new therapies. Epidermal growth factor receptor (EGFR) is over-expressed in ES; using preclinical models, we examined the ES EGFR role and assessed anti-ES EGFR blockade effects, alone and with mTOR inhibition. Experimental Design: EGFR and mTOR expression/activation was examined via tissue microarray (n = 27 human ES specimens; immunohistochemistry) and in human ES cell lines (Western blot and quantitative reverse transcriptase PCR). Cell proliferation, survival, migration, and invasion effects of EGFR and mTOR activation treated with erlotinib (anti-EGFR small-molecule inhibitor) alone and combined with rapamycin were assessed in cell culture assays. In vivo growth effects of erlotinib alone or with rapamycin were evaluated using severe combined immunodeficient mouse ES xenograft models. Results: EGFR was expressed and activated in ES specimens and cell lines. EGFR activation increased ES cell proliferation, motility, and invasion and induced cyclin D1, matrix metalloproteinase (MMP) 2, and MMP9 expression. EGFR blockade inhibited these processes and caused significant cytostatic ES growth inhibition in vivo. mTOR pathway activation at varying levels was identified in all tissue microarray-evaluable ES tissues; 88% of samples had no or reduced PTEN expression. Similarly, both ES cell lines showed enhanced mTOR activity; VAESBJ cells exhibited constitutive mTOR activation uncoupled from EGFR signaling. Most importantly, combined erlotinib/rapamycin resulted in synergistic anti-ES effects in vitro and induced superior tumor growth inhibition in vivo versus single agent administration. Conclusions: EGFR and mTOR signaling pathways are deregulated in ES. Preclinical ES model-derived insights suggest that combined inhibition of these targets might be beneficial, supporting evaluations in clinical trials.

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