Efficacy of targeted AKT inhibition in genetically engineered mouse models of PTEN-deficient prostate cancer

Oncotarget
Marco A De VelascoHirotsugu Uemura

Abstract

The PI3K/AKT pathway is frequently altered in advanced human prostate cancer mainly through the loss of functional PTEN, and presents as potential target for personalized therapy. Our aim was to determine the therapeutic potential of the pan-AKT inhibitor, AZD5363, in PTEN-deficient prostate cancer. Here we used a genetically engineered mouse (GEM) model of PTEN-deficient prostate cancer to evaluate the in vivo pharmacodynamic and antitumor activity of AZD5363 in castration-naïve and castration-resistant prostate cancer. An additional GEM model, based on the concomitant inactivation of PTEN and Trp53 (P53), was established as an aggressive model of advanced prostate cancer and was used to further evaluate clinically relevant endpoints after treatment with AZD5363. In vivo pharmacodynamic studies demonstrated that AZD5363 effectively inhibited downstream targets of AKT. AZD5363 monotherapy significantly reduced growth of tumors in castration-naïve and castration-resistant models of PTEN-deficient prostate cancer. More importantly, AZD5363 significantly delayed tumor growth and improved overall survival and progression-free survival in PTEN/P53 double knockout mice. Our findings demonstrate that AZD5363 is effective against GEM m...Continue Reading

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Citations

Jan 11, 2018·The Aging Male : the Official Journal of the International Society for the Study of the Aging Male·Norelia TorrealbaMar Royuela
Jun 4, 2019·International Journal of Molecular Sciences·Zsombor Melegh, Sebastian Oltean
May 8, 2018·International Journal of Molecular Sciences·Ekaterina NevedomskayaBernard Haendler
Nov 2, 2016·Cancer·Edoardo Francini, Mary-Ellen Taplin
Oct 28, 2020·Cells·Daniel J TurnhamHelen B Pearson

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Methods Mentioned

BETA
xenograft
PCR
imaging techniques
biopsy

Software Mentioned

Systat
SigmaPlot
ImageJ

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