Evaluation of in vivo responses of sorafenib therapy in a preclinical mouse model of PTEN-deficient of prostate cancer.
Evaluation of in vivo responses of sorafenib therapy in a preclinical mouse model of PTEN-deficient of prostate cancer.
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DOI：
10.1186/s12967-015-0509-x
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发表时间：
2015-05-08
影响因子：
7.4
通讯作者：
Uemura H
中科院分区：
文献类型：
--
作者：
Yamamoto Y;De Velasco MA;Kura Y;Nozawa M;Hatanaka Y;Oki T;Ozeki T;Shimizu N;Minami T;Yoshimura K;Yoshikawa K;Nishio K;Uemura H
尽管最近晚期前列腺癌的治疗取得了进展，但结果仍然很差。这种疗效的缺乏促使了替代治疗策略的发展。在本研究中，我们研究了多激酶抑制剂索拉非尼在基因工程小鼠前列腺癌模型中的作用，并探讨了与mTOR抑制剂依维莫司的合理联合。利用条件性前列腺特异性pten缺陷敲除小鼠来测定索拉非尼的药效学和化学预防作用。该小鼠模型还用于检测索拉非尼单独或与依维莫司联合的治疗效果。通过比较降低肿瘤负荷、增殖、血管生成和诱导细胞凋亡来评估临床前疗效。通过免疫组织化学、TUNEL和western blot检测分子反应。药理学分析显示，单剂量索拉非尼在30-60 mg/kg剂量下降低PI3K/AKT/mTOR信号轴的激活，但激活JAK/STAT3信号。裂解casapase-3水平呈剂量依赖性增加。化学预防研究表明，长期给药索拉非尼能够通过减少癌细胞增殖、血管生成和诱导细胞凋亡来抑制肿瘤进展。在已建立的castration-naïve和去势抵抗性前列腺癌的干预模型中，索拉非尼治疗提供了适度但统计学上不显著的肿瘤负担减少。然而，索拉非尼显著抑制癌细胞增殖和MVD，但对诱导凋亡的影响很小。有趣的是，索拉非尼增加了雄激素受体p-GSK3β和p-ERK1/2在去势抵抗性前列腺癌中的表达水平。在两种干预模式中，联合治疗均表现出比单一治疗更强的抗肿瘤效果的明显趋势。值得注意的是，索拉非尼和依维莫司联合治疗在去势抵抗性前列腺癌中克服了单药治疗的治疗逃避。总之，我们提供了索拉非尼治疗在前列腺癌临床相关模型中的分子反应的见解，并为基于多激酶抑制剂与mTOR抑制剂联合使用治疗晚期前列腺癌的靶向治疗策略的开发提供了临床前证据。本文的在线版本（doi:10.1186/s12967-015-0509-x）包含补充材料，可供授权用户使用。
Despite recent advances in the treatment for advanced prostate cancer, outcomes remain poor. This lack of efficacy has prompted the development of alternative treatment strategies. In the present study we investigate the effects of the multikinase inhibitor sorafenib in a genetically engineered mouse model of prostate cancer and explore the rational combination with the mTOR inhibitor everolimus. Conditional prostate specific PTEN-deficient knockout mice were utilized to determine the pharmacodynamic and chemopreventive effects of sorafenib. This mouse model was also used to examine the therapeutic efficacy of sorafenib alone or in combination with everolimus. Preclinical efficacy was assessed by comparing the reduction of tumor burden, proliferation, angiogenesis and the induction of apoptosis. Molecular responses were assessed by immunohistochemical, TUNEL and western blot assays. Pharmacodynamic analysis revealed that a single dose of sorafenib decreased activation of the PI3K/AKT/mTOR signaling axis at doses of 30–60 mg/kg, but activated JAK/STAT3 signaling. Levels of cleaved casapase-3 increased in a dose dependent manner. Chemoprevention studies showed that chronic sorafenib administration was capable of inhibiting tumor progression through the reduction of cancer cell proliferation, angiogenesis and the induction of apoptosis. In intervention models of established castration-naïve and castration-resistant prostate cancer, treatment with sorafenib provided modest but statistically insignificant reduction in tumor burden. However, sorafenib significantly inhibited cancer cell proliferation and MVD but had minimal effects on the induction of apoptosis. Interestingly, the administration of sorafenib increased the expression levels of the androgen receptor, p-GSK3β and p-ERK1/2 in castration-resistant prostate cancers. In both intervention models, combination therapy demonstrated a clear tendency of enhanced antitumor effects over monotherapy. Notably, the treatment combination of sorafenib and everolimus overcame therapeutic escape from single agent therapy in castration-resistant prostate cancers. In summary, we provide insights into the molecular responses of sorafenib therapy in a clinically relevant model of prostate cancer and present preclinical evidence for the development of targeted treatment strategies based on the use of multikinase inhibitors in combination with mTOR inhibitors for the treatment of advanced prostate cancer. The online version of this article (doi:10.1186/s12967-015-0509-x) contains supplementary material, which is available to authorized users.
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影响因子：
11.5
作者：
Pignochino, Ymera;Dell'Aglio, Carmine;Grignani, Giovanni
通讯作者：
Grignani, Giovanni
影响因子：
3.9
作者：
Mariniello, Barbara;Rosato, Antonio;Mantero, Franco
通讯作者：
Mantero, Franco
影响因子：
4.7
作者：
De Velasco MA;Tanaka M;Yamamoto Y;Hatanaka Y;Koike H;Nishio K;Yoshikawa K;Uemura H
通讯作者：
Uemura H
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
158.5
作者：
Kantoff, Philip W.;Higano, Celestia S.;Young, J.
通讯作者：
Young, J.