title: Efficacy of targeted AKT inhibition in genetically engineered mouse models of PTEN-deficient prostate cancer.
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.
authors.affiliation: Department of Urology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.|Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Marco A
authors.initials: MA
authors.lastname: De Velasco
authors.affiliation: Department of Urology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Yurie
authors.initials: Y
authors.lastname: Kura
authors.affiliation: Division of Advanced Research Promotion Institute of Comprehensive Medical Research, Aichi Medical University, Nagakute, Aichi, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yoshikawa
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.affiliation: Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, UK.
authors.forename: Barry R
authors.initials: BR
authors.lastname: Davies
authors.affiliation: Department of Urology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Uemura
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005818:Genetic Engineering / Q000379:methods; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; D011758:Pyrroles; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; C575618:capivasertib
keywords: AKT inhibitor; PTEN; preclinical model; prostate cancer; targeted therapy