Autophagy is cellular process that can promote tumor survival during periods of metabolic and therapeutic stress. Inhibition of autophagy can promote senescence resulting in decreased tumor growth. Genetic alterations of PTEN and p53 are frequently present in advanced human prostate cancer and are associated with poor prognosis. In mouse models, the inactivation of PTEN leads to the development of prostate tumors that progress slowly, in part due to the induction of PTEN-(loss)-induced cellular senescence. Concomitant inactivation of both PTEN and P53 in prostate leads to the development of an aggressive cancer phenotype that can overcome PTEN-(loss)-induced cellular senescence and is characterized with accelerated growth, metastatic development and decreased survival. Published findings show that in some cancer models, the effects of autophagy inhibition are dependent on p53 status. In this study we assessed the effects of pharmacological inhibition of autophagy with chloroquine (CQ) on the growth and progression of mouse prostate tumors driven by the concomitant inactivation of PTEN and p53. CQ is a lysosomotropic agent that has widely used to impede autophagy and inhibit the growth of human tumor cells in vitro and in vivo. Genetically engineered mice with the conditional inactivation of PTEN and p53 were used to evaluate the antitumor effects and therapeutic benefit of CQ in a drug intervention model of prostate cancer. Twenty-seven-week-old PTEN/p53 double knockout mice bearing prostate tumors were randomized to control and oral CQ (100 mg/kg in drinking water) treatment groups. Progression-free survival was 145 days versus 161 days (P = 0.703) for control and CQ treated mice, respectively. Median overall survival was 170 days versus 147 days (P = 0.523) for control and CQ treated mice, respectively. Tumor burden assed by the median genitourinary tract weight was 2.42 grams versus 2.19 grams (P = 0.645) for control and CQ treated mice, respectively. Our molecular assays revealed that CQ failed to consistently inhibit autophagy in tumors at the present dose. Overall, our findings show that CQ alone did not provide treatment benefit in mouse prostate cancer with loss of p53.

Citation Format: Marco A. De Velasco, Koichi Sugimoto, Yurie Kura, Yuji Hatanaka, Yutaka Yamamoto, Takashi Oki, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Effects of oral chloroquine administration on a preclinical mouse model of PTEN/p53-deficient prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3538.

©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.