Abstract 5282: Preclinical efficacy of abiraterone plus capivasertib in mouse Pten-deficient prostate cancer
Authors: De Velasco Marco A. , Kura Yurie , Ando Naomi , Kuroka Keiko , Fujita Kazutoshi , Banno Eri , Sakai Kazuko , Nozawa Masahiro , Yoshimura Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: June 2022

Abstract
Prostate tumors are characterized with constitutively activated AKT signaling primarily through the loss of PTEN. Second generation antiandrogens such as abiraterone acetate have improved the survival of prostate cancer patients, however, resistance remains a problem and patients with PTEN-deficient tumors have poorer outcomes to abiraterone treatments. Moreover, PTEN-deficient tumors are also characterized with immunosuppressive tumor microenvironments. In this study we investigate the benefit of adding capivasertib, a potent pan-Akt inhibitor, to abiraterone therapy in a preclinical model of Pten-deficient prostate cancer and examine the antitumor efficacy and its influence on antitumor immunity. The temporal effects of abiraterone and capivasertib alone and as combination therapy were evaluated after one and four weeks of dosing in conditional transgenic mice harboring Pten-deficient prostate tumors. While abiraterone therapy alone reduced genitourinary tract weights, which contain both AR-sensitive normal accessory sex organs and prostate tumor, the treatment had no overall effect on prostate tumor burden. Mice treated with capivasertib monotherapy experienced tumor burden reductions of 8.2% and 15.6% at week 1 and 8, respectively, moreover, the treatment combination of abiraterone + capivasertib significantly improved the therapeutic effect with tumor burden reductions of 35.6% and 37.8% at weeks 1 and 4, respectively versus vehicle control. qRT-PCR analysis of Ar target genes showed decreased expression in mice treated with abiraterone. All treatment combinations showed increased gene expression levels of Casp3 in tumors from mice at week one but were greatest in those treated with abiraterone alone or in combination and increased expression levels were sustained only in the combination cohort at week four. Immunological profiling of tumors from mice treated with abiraterone + capivasertib using qRT-PCR-based panel of immune-related genes revealed enrichments in genes associated with phagocytosis, antigen processing and dendritic cell function. Examination of the tumor draining lymph nodes by flow cytometric analysis showed ~1.5-fold-increases in the abundance of migratory dendritic cells (CD11b+\CD11c+\XCR1+) in all pharmacologically treated mice (versus vehicle control) and remained elevated only in mice receiving capivasertib as monotherapy or combination at week four. Additionally, mice treated with combination therapy also had enrichments in genes sets associated to T cell, NK cell and as well as T cell activation, cytotoxicity, and interferon gamma signature. The findings from this study provide preclinical evidence for the efficacy of combination therapy with abiraterone plus capivasertib and provides insights into its immunomodulatory effects and influence on antitumor immunity.
Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Keiko Kuroka, Kazutoshi Fujita, Eri Banno, Kazuko Sakai, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura. Preclinical efficacy of abiraterone plus capivasertib in mouse Pten-deficient prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5282.