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.
Highlights
Androgen-deprivation therapy remains the primary treatment option for patients with metastatic prostate cancer
Our findings demonstrate that AZD5363 is effective against genetically engineered mouse (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 PTENdeficient prostate cancer
Our first aim was to determine the pharmacodynamic (PD) effects of AZD5363 in a preclinical model of prostate cancer that shares similar features and genetic alterations associated with the human disease
Summary
Androgen-deprivation therapy remains the primary treatment option for patients with metastatic prostate cancer. Most of these individuals will inevitably develop resistance and progress to a form of the disease referred to as castration-resistant prostate cancer (CRPC). A number of studies have focused on characterizing the molecular landscape of advanced prostate cancer to identify networks with potentially druggable targets that may aid in the development of better treatment strategies [4,5,6]. GEM are designed to recapitulate molecular and biological features of human cancer, and afford a number of features lacking in xenograft models, making it a choice animal model to assess the preclinical efficacy of novel therapeutic compounds [9]
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