Abstract 1845: Chloroquine demonstrates limited effectiveness in an autochthonous preclinical model of prostate cancer

Abstract

Abstract Chloroquine (CQ) is a well-known compound that is used for the treatment of malaria and certain autoimmune diseases. CQ can also block autophagy, an essential cellular process that is implicated with resistance to chemotherapy. Preclinical studies have demonstrated the anticancer effects of CQ and hydroxychloroquine when used in combination with other anticancer agents suggesting that blocking autophagy inhibits therapeutic resistance. However, recent data shows that CQ can have antitumor effects independent of autophagy. Furthermore, given the specific roles of autophagy during tumorigenesis, the therapeutic effects of CQ observed in xenograft studies may differ than those in an autochthonous tumor model. The aim of our study was to investigate the antitumor effects of CQ in an autochthonous tumor model and to determine if CQ could reverse therapeutic resistance through the induction of autophagy. To test this hypothesis we tested the therapeutic administration of CQ in a genetically engineered mouse model of prostate cancer driven by the conditional inactivation of PTEN. We also characterized the combinatorial effects of CQ in combination with additional molecular targeting that included mTOR (everolimus), AKT (AZD5363), MEK (Selumetinib; AZD6244/ARRY142886), 5α-reductase (dutasteride) inhibitors. Oral administration of CQ demonstrated antitumor activity and moderately, but significantly, inhibited growth PTEN-deficient prostate tumors in a drug intervention model. However, combination therapy with CQ did not enhance therapeutic efficacy over inhibitor monotherapy alone. Mice with PTEN-mutant castration-resistant prostate cancer (CRPC) are resistant to treatment with everolimus. Therefore, we tested whether blocking autophagy could restore sensitivity to everolimus in CRPC. Mice with mutant PTEN and ATG7, an autophagy regulatory gene, CRPC demonstrated increased sensitivity and activity to everolimus suggesting that defective autophagy restored resistance to everolimus. On, the contrary, the treatment the combination of CQ and everolimus failed to produce any treatment effects in PTEN-deficient/ATG7-wildtype CRPC. Our findings suggest that combinatorial strategies with CQ lack therapeutic efficacy in autochthonous tumors and might be ineffective in the clinical setting. Citation Format: Yurie Kura, Marco A. De Velasco, Naomi Ando, Emiko Fukushima, Barry R. Davies, Dennis Huzdar, Yutaka Yamamoto, Yuji Hatanaka, Takashi Oki, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Chloroquine demonstrates limited effectiveness in an autochthonous preclinical model of prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1845. doi:10.1158/1538-7445.AM2015-1845