Development of apratoxin S10 (Apra S10) as an anti-pancreatic cancer agent and its preliminary evaluation in an orthotopic patient-derived xenograft (PDX) model.
Development of apratoxin S10 (Apra S10) as an anti-pancreatic cancer agent and its preliminary evaluation in an orthotopic patient-derived xenograft (PDX) model.
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DOI：
10.1007/s10637-018-0647-0
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发表时间：
2019-04
影响因子：
3.4
通讯作者：
Luesch H
中科院分区：
文献类型：
--
作者：
Cai W;Ratnayake R;Gerber MH;Chen QY;Yu Y;Derendorf H;Trevino JG;Luesch H
尽管癌症治疗领域取得了重大进展，但胰腺癌(PC)的发病率仍在不断上升。这种负担增加的一个可能机制是独特的肿瘤微环境和基因突变导致的药物输送和耐药性受损。蜂毒素是一种有效的抗癌药物和共翻译易位抑制剂，具有潜在的治疗应用前景，可用于治疗具有活跃分泌途径的癌症。在这里，我们开发了apratoxin S10(APRA S10)作为一种抗胰腺癌药物，它可以有效地抑制已建立的和患者来源的原发胰腺癌细胞的生长。我们通过下调多受体酪氨酸激酶，抑制生长因子和细胞因子的分泌，验证了其对胰腺癌细胞的作用机制。APRA S10还抑制间质细胞分泌的多种细胞因子，提示APRA S10不仅能抑制胰腺癌细胞的分泌，还能降低肿瘤微环境中活跃的其他细胞类型分泌的因子水平。由于APRA S10在胰腺组织中的分布表明其在胰腺组织中高度浓缩，因此，首次将模拟人胰腺肿瘤微环境的原位胰腺患者来源的异种移植小鼠模型用于APRATOX研究。APRA S10在该胰腺癌模型中显示出良好的抗肿瘤作用，这种作用是通过抗增殖作用来实现的。
Despite the significant progress in the field of cancer therapeutics, the incidence of pancreatic cancer (PC) has continuously increased. One possible mechanism for this increasing burden is impaired drug delivery and drug resistance resulting from a unique tumor microenvironment and genetic mutations. Apratoxins are potent anticancer agents and cotranslational translocation inhibitors with potential therapeutic applications to treat cancers with active secretory pathways. Here, we developed apratoxin S10 (Apra S10) as an anti-pancreatic cancer agent which potently inhibited the growth of both established and patient-derived primary pancreatic cancer cells. We validated its mechanism of action on pancreatic cancer cells by demonstrating the downregulation of multiple receptor tyrosine kinases and inhibition of growth factor and cytokine secretion. Apra S10 also inhibited a number of cytokines from stromal cells, suggesting that Apra S10 not only inhibited pancreatic cancer cell secretion, but also reduced the level of factors secreted by other cell types active within the tumor microenvironment. As Apra S10 tissue distribution indicated its high enrichment in pancreas tissue, an orthotopic pancreatic patient-derived xenograft mouse model that closely mimics the human pancreatic tumor microenvironment was for the first time used in apratoxin studies. Apra S10 showed promising antitumor effect in this pancreatic cancer model and this effect was mediated through anti-proliferation effects.
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影响因子：
8.6
作者：
Paatero, Anja O.;Kellosalo, Juho;Paavilainen, Ville O.
通讯作者：
Paavilainen, Ville O.
影响因子：
64.8
作者：
Straussman, Ravid;Morikawa, Teppei;Shee, Kevin;Barzily-Rokni, Michal;Qian, Zhi Rong;Du, Jinyan;Davis, Ashli;Mongare, Margaret M.;Gould, Joshua;Frederick, Dennie T.;Cooper, Zachary A.;Chapman, Paul B.;Solit, David B.;Ribas, Antoni;Lo, Roger S.;Flaherty, Keith T.;Ogino, Shuji;Wargo, Jennifer A.;Golub, Todd R.
通讯作者：
Golub, Todd R.
影响因子：
2.5
作者：
Chandra R;Liddle RA
通讯作者：
Liddle RA
影响因子：
6
作者：
Pham, Kien;Delitto, Daniel;Trevino, Jose G.
通讯作者：
Trevino, Jose G.
影响因子：
45.3
作者：
Moore, Malcolm J.;Goldstein, David;Parulekar, Wendy
通讯作者：
Parulekar, Wendy