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Oncotarget. 2016 Mar 29;7(13):15959-76. doi: 10.18632/oncotarget.7557.

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

Author information

1
Department of Urology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
2
Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
3
Division of Advanced Research Promotion Institute of Comprehensive Medical Research, Aichi Medical University, Nagakute, Aichi, Japan.
4
Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, UK.

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 models of PTEN-deficient prostate cancer and provide lines of evidence to support further investigation into the development of treatment strategies targeting AKT for the treatment of PTEN-deficient prostate cancer.

KEYWORDS:

AKT inhibitor; PTEN; preclinical model; prostate cancer; targeted therapy

PMID:
26910118
PMCID:
PMC4941290
DOI:
10.18632/oncotarget.7557
[Indexed for MEDLINE]
Free PMC Article

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