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Synergistic activity of the mTOR inhibitor ridaforolimus and the antiandrogen bicalutamide in prostate cancer models

  • Authors:
    • Rachel M. Squillace
    • David Miller
    • Scott D. Wardwell
    • Frank Wang
    • Tim Clackson
    • Victor M. Rivera
  • View Affiliations / Copyright

    Affiliations: Department of Biology, ARIAD Pharmaceuticals Inc., Cambridge, MA, USA, Department of Pharmacology, ARIAD Pharmaceuticals Inc., Cambridge, MA, USA
    Copyright: © Squillace et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].
  • Pages: 425-432
    |
    Published online on: May 18, 2012
       https://doi.org/10.3892/ijo.2012.1487
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Abstract

Although androgen ablation therapy is the foundation of current prostate cancer treatment, most patients ultimately develop castration-resistant disease. One proposed mechanism to account for androgen receptor (AR) activity in the castrate environment is via crosstalk with other signaling pathways. Specifically, reciprocal interactions between the AKT/mTOR and AR pathways have been implicated in prostate cancer progression. Here, we used the potent inhibitor ridaforolimus to target mTOR signaling alone and in combination with AR blockade by bicalutamide to examine the effect of abrogating these signaling pathways. Ridaforolimus treatment inhibited the proliferation of all six prostate cancer cell lines examined with the greatest sensitivity associated with loss of PTEN and elevated AKT/mTOR pathway activity. Dual inhibition of the AR and mTOR signaling pathways provided further benefit with the ridaforolimus-bicalutamide combination producing synergistic antiproliferative effects in prostate cancer cells in vitro when compared with each agent alone. Pharmacodynamic analysis confirmed that combination treatment resulted in full inhibition of each of the respective pathways. Importantly, the ridaforolimus-bicalutamide combination exhibited potent antitumor activity with parallel reductions in plasma PSA levels in vivo. Taken together, ridaforolimus exhibited potent antiproliferative and antitumor activity in prostate cancer models and the addition of bicalutamide represents a potentially effective combination strategy for patient therapy.
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Copy and paste a formatted citation
Spandidos Publications style
Squillace RM, Miller D, Wardwell SD, Wang F, Clackson T and Rivera VM: Synergistic activity of the mTOR inhibitor ridaforolimus and the antiandrogen bicalutamide in prostate cancer models. Int J Oncol 41: 425-432, 2012.
APA
Squillace, R.M., Miller, D., Wardwell, S.D., Wang, F., Clackson, T., & Rivera, V.M. (2012). Synergistic activity of the mTOR inhibitor ridaforolimus and the antiandrogen bicalutamide in prostate cancer models. International Journal of Oncology, 41, 425-432. https://doi.org/10.3892/ijo.2012.1487
MLA
Squillace, R. M., Miller, D., Wardwell, S. D., Wang, F., Clackson, T., Rivera, V. M."Synergistic activity of the mTOR inhibitor ridaforolimus and the antiandrogen bicalutamide in prostate cancer models". International Journal of Oncology 41.2 (2012): 425-432.
Chicago
Squillace, R. M., Miller, D., Wardwell, S. D., Wang, F., Clackson, T., Rivera, V. M."Synergistic activity of the mTOR inhibitor ridaforolimus and the antiandrogen bicalutamide in prostate cancer models". International Journal of Oncology 41, no. 2 (2012): 425-432. https://doi.org/10.3892/ijo.2012.1487
Copy and paste a formatted citation
x
Spandidos Publications style
Squillace RM, Miller D, Wardwell SD, Wang F, Clackson T and Rivera VM: Synergistic activity of the mTOR inhibitor ridaforolimus and the antiandrogen bicalutamide in prostate cancer models. Int J Oncol 41: 425-432, 2012.
APA
Squillace, R.M., Miller, D., Wardwell, S.D., Wang, F., Clackson, T., & Rivera, V.M. (2012). Synergistic activity of the mTOR inhibitor ridaforolimus and the antiandrogen bicalutamide in prostate cancer models. International Journal of Oncology, 41, 425-432. https://doi.org/10.3892/ijo.2012.1487
MLA
Squillace, R. M., Miller, D., Wardwell, S. D., Wang, F., Clackson, T., Rivera, V. M."Synergistic activity of the mTOR inhibitor ridaforolimus and the antiandrogen bicalutamide in prostate cancer models". International Journal of Oncology 41.2 (2012): 425-432.
Chicago
Squillace, R. M., Miller, D., Wardwell, S. D., Wang, F., Clackson, T., Rivera, V. M."Synergistic activity of the mTOR inhibitor ridaforolimus and the antiandrogen bicalutamide in prostate cancer models". International Journal of Oncology 41, no. 2 (2012): 425-432. https://doi.org/10.3892/ijo.2012.1487
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