Abstract B19: Induction of apoptosis and antitumor activity of the AKT inhibitor AZD5363 is enhanced by combination with hormonal therapies in preclinical models of prostate cancer

Abstract

Abstract Activation of AKT by mechanisms including loss of the tumor suppressors PTEN and INPP4B is very common in prostate cancer, and has been correlated with poor prognosis and progression to androgen independent disease. Recently, a reciprocal feedback mechanism has been shown to occur between the androgen and AKT signalling axes in prostate cancer models. AZD5363 monotherapy induced apoptosis and inhibited growth of PTEN null, AR+ prostate cancer cell lines including LNCaP, C4-2 and a flutamide resistant variant of PC346C (GI50 10 – 100 nM), and showed moderate anti-proliferative activity in AR amplified, PTEN wild type VCaP cells (GI50 ∼ 1 μM). The PTEN wild type, AR negative DU-145, BPH1 and RWPE1 cell lines were relatively resistant. Monotherapy AZD5363 also caused dosedependent growth inhibition of the PTEN null, AR+ HID28 prostate cancer explant model in vivo. Treatment with AZD5363 increased expression of a panel of androgen regulated genes in LNCaP cells, whereas the same panel of genes was down-regulated when AZD5363 was combined with the novel anti-androgen MDV-3100. Combination of AZD5363 with MDV-3100 resulted in greater inhibition of growth and induction of apoptosis in vitro than monotherapy treatment with these agents, indicating a synergistic interaction. Moreover, combination of AZD5363 and bicalutamide resulted in greater efficacy than AZD5363 monotherapy in LNCaP xenografts in vivo. The data show that whilst AZD5363 has considerable monotherapy activity in AR+/PTEN null prostate cancer models, the combination with anti-androgens merits further evaluation as a possible means to achieve greater anti-tumor activity. AZD5363 is currently in Phase 1 clinical trials. Citation Format: Claire Crafter, Barry R. Davies, Christian Thomas, Francois Lamoureux, Hannah Greenwood, Juan M. Garcia-Martinez, Lorraine Mooney, Sabina Cosulich, Martin Gleave, Amina Zoubeidi. Induction of apoptosis and antitumor activity of the AKT inhibitor AZD5363 is enhanced by combination with hormonal therapies in preclinical models of prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B19.