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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleDrug Discovery and Translational Medicine

Multimodal Biomarker Investigation on Efficacy and Mechanism of Action for the Mammalian Target of Rapamycin Inhibitor, Temsirolimus, in a Preclinical Mammary Carcinoma OncoMouse Model: A Translational Medicine Study in Support for Early Clinical Development

Xinkang Wang, Yutian Zhan, Lei Zhao, John Alvarez, Inder Chaudhary, Bin-Bing Zhou, Robert T. Abraham and Giora Z. Feuerstein
Journal of Pharmacology and Experimental Therapeutics November 2011, 339 (2) 421-429; DOI: https://doi.org/10.1124/jpet.111.185249
Xinkang Wang
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Yutian Zhan
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Lei Zhao
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John Alvarez
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Inder Chaudhary
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Bin-Bing Zhou
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Robert T. Abraham
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Giora Z. Feuerstein
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Abstract

The mammalian target of rapamycin (mTOR) has proven to be a valid therapeutic target in a number of human cancers, and it is a candidate for clinical trials in human breast cancer. We report on a biomarker-based translational medicine approach to assess the efficacy and mechanism of action for the mTOR inhibitor temsirolimus (CCI-779) in a mammary carcinoma OncoMouse model [polyomavirus middle T antigen (PyMT)]. The mTOR signaling pathway biomarkers were assessed using a reverse-phase protein array. Pharmacokinetics studies were conducted in both the tumor and plasma compartments. Pharmacodynamic biomarkers for compound-target engagement of tumor phospho-S6 proteins were assayed by Western blot. Temsirolimus (intravenously once a week for 2 weeks) was administered in both early and advanced stages of tumors. Biomarkers for temsirolimus effects on tumor progression were assessed by three-dimensional ultrasound imaging in combination with immunohistochemistry to assess vascular density (Texas red-dextran and CD31 immunostaining) and macrophage burden (F4/80 antigen). Tumor growth was significantly arrested in temsirolimus (25 ± 14% from 8 to 10 weeks, p < 0.05, and 26 ± 17% from 11 to 13 weeks, p < 0.01), compared with 493 ± 160 and 376 ± 50% increases, respectively, in vehicle-treated groups. Temsirolimus reduced tumor vascular density, 36 to 48 and 58 to 60%, p < 0.05, by the Texas red-dextran method or CD31-positive vessel count, respectively. Temsirolimus reduced tumor macrophage burden by 46% at 13 weeks (p < 0.05). Temsirolimus inhibited (p < 0.05) the phosphoproteins S6 pS235/236 and S6 pS240/244 up to 81 and 87%, respectively. We conclude that the multimodal biomarkers of temsirolimus efficacy and mechanism of action (phosphoproteins) strongly suggest that it might translate to therapeutic efficacy in human tumors that bear congruency to features present in the mammary carcinoma of PyMT tumors.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.111.185249.

  • ABBREVIATIONS:

    mTOR
    mammalian target of rapamycin
    PyMT
    polyomavirus middle T antigen
    PI3K
    phosphatidylinositol-3 kinase
    S6K
    ribosomal S6 kinase
    MMTV
    mouse mammary tumor virus
    IHC
    immunohistochemistry
    PK
    pharmacokinetic
    VEGF
    vascular endothelial growth factor
    DAPI
    4,6-diamidino-2-phenylindole.

  • Received June 23, 2011.
  • Accepted August 10, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 339 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 339, Issue 2
1 Nov 2011
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Research ArticleDrug Discovery and Translational Medicine

Translational Medicine Study of Temsirolimus in PyMT Mice

Xinkang Wang, Yutian Zhan, Lei Zhao, John Alvarez, Inder Chaudhary, Bin-Bing Zhou, Robert T. Abraham and Giora Z. Feuerstein
Journal of Pharmacology and Experimental Therapeutics November 1, 2011, 339 (2) 421-429; DOI: https://doi.org/10.1124/jpet.111.185249

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Research ArticleDrug Discovery and Translational Medicine

Translational Medicine Study of Temsirolimus in PyMT Mice

Xinkang Wang, Yutian Zhan, Lei Zhao, John Alvarez, Inder Chaudhary, Bin-Bing Zhou, Robert T. Abraham and Giora Z. Feuerstein
Journal of Pharmacology and Experimental Therapeutics November 1, 2011, 339 (2) 421-429; DOI: https://doi.org/10.1124/jpet.111.185249
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