Notch signaling pathway targeted therapy suppresses tumor progression and metastatic spread in pancreatic cancer.
Notch signaling pathway targeted therapy suppresses tumor progression and metastatic spread in pancreatic cancer.
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DOI：
10.1016/j.canlet.2013.01.054
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发表时间：
2013-07-10
期刊：
影响因子：
9.7
通讯作者：
Rajeshkumar, N. V.
中科院分区：
文献类型：
--
作者：
Yabuuchi, Shinichi;Pai, Shweta G.;Campbell, Nathaniel R.;de Wilde, Roeland F.;De Oliveira, Elizabeth;Korangath, Preethi;Streppel, Mirte M.;Rasheed, Zeshaan A.;Hidalgo, Manuel;Maitra, Anirban;Rajeshkumar, N. V.
胰腺导管腺癌（PDA）仍然是一种致命的人类恶性肿瘤，历史上治疗成功率有限。异常Notch信号传导（其需要γ-分泌酶的组成性激活）在PDA的起始和进展中的作用已明确，并且该途径的抑制剂目前处于临床试验中。在此，我们研究了PF-03084014（一种选择性γ-分泌酶抑制剂）单独给药和与吉西他滨联合给药在胰腺癌异种移植物中的体内治疗作用。PF-03084014处理抑制了细胞核Notch 1胞内结构域和Notch靶点Hes-1和Hey-1的裂解。吉西他滨治疗显示出良好的反应，但不能诱导肿瘤消退和靶向肿瘤驻留的癌症干细胞（CD 24 + CD 44+和ALDH+肿瘤细胞）。PF-03084014和吉西他滨联合给药导致3/4个皮下植入异种移植模型的肿瘤消退。PF-03084014与吉西他滨联合使用减少了推定的癌症干细胞，表明PF-03084014靶向胰腺肿瘤中特别危险和有弹性的癌症干细胞。药物治疗后绘制的肿瘤再生长曲线表明，联合治疗的效果比吉西他滨更持久。值得注意的是，在高度侵袭性原位模型中，与吉西他滨治疗相比，PF-03084014和吉西他滨联合治疗可有效诱导细胞凋亡、抑制肿瘤细胞增殖和血管生成，从而减弱原发性肿瘤生长并控制转移性播散。总之，我们的临床前数据表明，PF-03084014与吉西他滨联合治疗PDA具有更强的抗肿瘤活性，并为进一步研究该联合治疗PDA提供了依据。
Pancreatic ductal adenocarcinoma (PDA) remains a lethal human malignancy with historically limited success in treatment. The role of aberrant Notch signaling, which requires the constitutive activation of γ-secretase, in the initiation and progression of PDA is well defined and inhibitors of this pathway are currently in clinical trials. Here we investigated the in vivo therapeutic effect of PF-03084014, a selective γ-secretase inhibitor, alone and in combination with gemcitabine in pancreatic cancer xenografts. PF-03084014 treatment inhibited the cleavage of nuclear Notch 1 intracellular domain and Notch targets Hes-1 and Hey-1. Gemcitabine treatment showed good response but not capable of inducing tumor regressions and targeting the tumor-resident cancer stem cells (CD24+CD44+ and ALDH+ tumor cells). A combination of PF-03084014 and gemcitabine treatment resulted tumor regression in 3 of 4 subcutaneously implanted xenograft models. PF-03084014, and in combination with gemcitabine reduced putative cancer stem cells, indicating that PF-03084014 target the especially dangerous and resilient cancer stem cells within pancreatic tumors. Tumor re-growth curves plotted after drug treatments demonstrated that the effect of the combination therapy was sustainable than that of gemcitabine. Notably, in a highly aggressive orthotopic model, PF-03084014 and gemcitabine combination was effective in inducing apoptosis, inhibition of tumor cell proliferation and angiogenesis, resulting in the attenuation of primary tumor growth as well as controlling metastatic dissemination, compared to gemcitabine treatment. In summary, our preclinical data suggest that PF-03084014 has greater anti-tumor activity in combination with gemcitabine in PDA and provides rationale for the further investigation of this combination in PDA.
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DOI：
10.1073/pnas.0810111105
发表时间：
2008-12-02
影响因子：
11.1
作者：
Jean-Paul, De La O.;Emerson, Lyska L.;Murtaugh, L. Charles
通讯作者：
Murtaugh, L. Charles
影响因子：
11.2
作者：
Li, Chenwei;Heidt, David G.;Simeone, Diane M.
通讯作者：
Simeone, Diane M.
DOI：
10.1158/1078-0432.ccr-09-2823
发表时间：
2010-06-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Pannuti A;Foreman K;Rizzo P;Osipo C;Golde T;Osborne B;Miele L
通讯作者：
Miele L
DOI：
10.4161/cc.8.12.8744
发表时间：
2009-06-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
De La O JP;Murtaugh LC
通讯作者：
Murtaugh LC
影响因子：
64.5
作者：
Gupta PB;Onder TT;Jiang G;Tao K;Kuperwasser C;Weinberg RA;Lander ES
通讯作者：
Lander ES