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Prostate Cancer

High Efficacy of Combination Therapy Using PI3K/AKT Inhibitors with Androgen Deprivation in Prostate Cancer Preclinical Models

By: Rute B. Marques a lowast , Ashraf Aghai a , Corrina M.A. de Ridder a , Debra Stuurman a , Sander Hoeben a , Agnes Boer a , Rebecca P. Ellston c , Simon T. Barry c , Barry R. Davies c , Jan Trapman b and Wytske M. van Weerden a

European Urology, Volume 67 Issue 6, June 2015, Pages 1177-1185

Published online: 01 June 2015

Keywords: Prostate cancer, Targeted therapy, PI3K inhibitor, AKT inhibitor, Androgen receptor

Abstract Full Text Full Text PDF (1,1 MB) Patient Summary

Abstract

Background

The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT pathway is frequently activated during prostate cancer (PCa) progression through loss or mutation of the phosphatase and tensin homolog (PTEN) gene. Following the androgen receptor (AR) pathway, it is the second major driver of PCa growth.

Objective

To assess efficacy of novel PI3K/AKT-targeted therapies in PCa models, as a single agent and in combination with androgen deprivation.

Design, setting, and participants

Twelve human PCa cell lines were tested in vitro for sensitivity to the AKT inhibitor AZD5363 and the PI3K beta/delta inhibitor AZD8186. The combination of AZD5363 and AZD8186 with castration was evaluated in vivo in PTEN-negative versus PTEN-positive patient-derived xenografts. Tumors and plasma were collected for biomarker analysis.

Outcome measurements and statistical analysis

In vitro growth inhibition was determined by methylthiazolyldiphenyl-tetrazolium bromide assay. In vivo efficacy was monitored by caliper measurements of subcutaneous tumor volume. PI3K/AKT and AR pathway activity was analyzed by Western blot, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction.

Results and limitations

AZD5363 and AZD8186 inhibited in vitro growth of 10 of 12 and 7 of 12 PCa cell lines, respectively, with increased sensitivity under androgen depletion. In vivo, AZD5363 and AZD8186 as single agents significantly inhibited growth of PTEN-negative PC346C xenografts compared to placebo by 60% and 66%, respectively. Importantly, combination of either agent with castration resulted in long-lasting tumor regression, which persisted after treatment cessation. Expression of AR-target genes kallikrein-related peptidase 3 (KLK3, also known asPSA); transmembrane protease, serine 2 (TMPRSS2); and FK506 binding protein 5 (FKBP5) was upregulated after PI3K/AKT inhibition. Neither compound inhibited tumor growth in the PTEN-positive PC310 model.

Conclusions

Combination with hormonal therapy improved efficacy of PI3K/AKT-targeted agents in PTEN-negative PCa models. Upregulation of AR-target genes upon PI3K/AKT inhibition suggests a compensatory crosstalk between the PI3K–AR pathways. These data strongly advocate for further clinical evaluation.

Patient summary

Inactivation of thePTENgene is a common event promoting prostate cancer (PCa) progression. This preclinical study illustrates the potent anticancer activity of novel PTEN-targeted drugs on PCa models, particularly in combination with hormonal therapy.

Take Home Message

AZD5363 and AZD8186 are two novel, orally bioavailable PI3K/AKT inhibitors with potent antitumor activity in prostate cancer preclinical models. Cotargeting the PI3K and AR pathways induced complete tumor regression in PTEN-negative, patient-derived xenografts and was required for maximal therapeutic efficacy.

Keywords: Prostate cancer, Targeted therapy, PI3K inhibitor, AKT inhibitor, Androgen receptor.

Footnotes

a Department of Urology, Erasmus MC, University Medical Center Rotterdam, The Netherlands

b Department of Pathology, Erasmus MC, University Medical Center Rotterdam, The Netherlands

c Oncology Innovative Medicines, AstraZeneca, Macclesfield, UK

lowast Corresponding author. Department of Urology, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands. Tel. +31 107043922. Fax: +31 107044661.

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