Multimodal Treatment Eliminates Cancer Stem Cells and Leads to Long-Term Survival in Primary Human Pancreatic Cancer Tissue Xenografts.
Multimodal Treatment Eliminates Cancer Stem Cells and Leads to Long-Term Survival in Primary Human Pancreatic Cancer Tissue Xenografts.
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DOI：
10.1371/journal.pone.0066371
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Heeschen C
中科院分区：
文献类型：
--
作者：
Hermann PC;Trabulo SM;Sainz B Jr;Balic A;Garcia E;Hahn SA;Vandana M;Sahoo SK;Tunici P;Bakker A;Hidalgo M;Heeschen C
尽管进行了大量的研究工作，但胰腺导管腺癌仍然是世界上最致命的恶性肿瘤之一。我们和其他人之前已经将肿瘤内的胰腺癌干细胞亚群确定为关键的治疗靶点，并进一步表明，肿瘤基质不仅是成功给药的限制性屏障，而且还是癌症干细胞的旁分泌利基。因此，我们开始大规模研究联合化疗、Hedgehog通路抑制和mTOR抑制在临床前小鼠胰腺癌模型中的作用。在一组近200例皮下和原位植入的原发人类原发肿瘤异种移植中进行前瞻性和随机试验。联合靶向高度耐药的癌症干细胞及其更多分化的后代，以及通过靶向间质和增强化疗药物的组织渗透来消除肿瘤微环境，可以显著延长人类胰腺癌临床前模型的生存时间。最显著的疗效是在对吉西他滨耐药的患者来源的肿瘤中观察到的。有趣的是，建议的三联疗法可以通过使用聚乙二醇化的吉西他滨配方来进一步增强，这大大增加了它的生物利用度和组织渗透率，从而进一步改善了总体结果。这种多模式治疗策略应该在临床环境中进一步探索，因为它的成功最终可能会改善胰腺导管腺癌患者的不良预后。
In spite of intense research efforts, pancreatic ductal adenocarcinoma remains one of the most deadly malignancies in the world. We and others have previously identified a subpopulation of pancreatic cancer stem cells within the tumor as a critical therapeutic target and additionally shown that the tumor stroma represents not only a restrictive barrier for successful drug delivery, but also serves as a paracrine niche for cancer stem cells. Therefore, we embarked on a large-scale investigation on the effects of combining chemotherapy, hedgehog pathway inhibition, and mTOR inhibition in a preclinical mouse model of pancreatic cancer. Prospective and randomized testing in a set of almost 200 subcutaneous and orthotopic implanted whole-tissue primary human tumor xenografts. The combined targeting of highly chemoresistant cancer stem cells as well as their more differentiated progenies, together with abrogation of the tumor microenvironment by targeting the stroma and enhancing tissue penetration of the chemotherapeutic agent translated into significantly prolonged survival in preclinical models of human pancreatic cancer. Most pronounced therapeutic effects were observed in gemcitabine-resistant patient-derived tumors. Intriguingly, the proposed triple therapy approach could be further enhanced by using a PEGylated formulation of gemcitabine, which significantly increased its bioavailability and tissue penetration, resulting in a further improved overall outcome. This multimodal therapeutic strategy should be further explored in the clinical setting as its success may eventually improve the poor prognosis of patients with pancreatic ductal adenocarcinoma.
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影响因子：
29.4
作者：
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