An orally bioavailable small-molecule inhibitor of Hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancer.
An orally bioavailable small-molecule inhibitor of Hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancer.
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DOI：
10.1158/1535-7163.mct-08-0573
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发表时间：
2008-09
影响因子：
5.7
通讯作者：
Maitra A
中科院分区：
文献类型：
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作者：
Feldmann G;Fendrich V;McGovern K;Bedja D;Bisht S;Alvarez H;Koorstra JB;Habbe N;Karikari C;Mullendore M;Gabrielson KL;Sharma R;Matsui W;Maitra A
最近的证据表明，阻断异常的 Hedgehog 信号传导可以作为胰腺癌的治疗策略。我们之前使用原型 Hedgehog 小分子拮抗剂环巴明进行的研究表明，在自发转移的原位异种移植模型中，Hedgehog 阻断对全身转移具有显着抑制作用。环巴明是一种天然化合物，药代动力学欠佳，阻碍了临床转化。在本研究中，使用体外和体内模型系统测试了一种新型口服生物可利用的小分子 Hedgehog 抑制剂 IPI-269609。用 IPI-269609 对胰腺癌细胞系进行体外处理，类似于使用环杷明观察到的效果（即 Gli 响应报告基因敲低、Hedgehog 靶基因 Gli1 和 Ptch 的下调，以及软琼脂中细胞迁移和集落形成的消除）。单药 IPI-269609 深度抑制由人胰腺癌细胞系建立的原位异种移植物中的全身转移，尽管 Hedgehog 阻断对原发肿瘤体积的影响很小。在治疗的原发性肿瘤中观察到的唯一可辨别的表型是乙醛脱氢酶亮细胞群的显着减少，我们之前已将其鉴定为胰腺癌中的克隆肿瘤起始群。使用 IPI-269609 选择性离体去除乙醛脱氢酶亮细胞，伴随着无胸腺小鼠肿瘤植入率的显着降低。药物阻断异常的 Hedgehog 信号可能被证明是抑制胰腺癌全身转移的有效治疗策略，可能是通过靶向具有肿瘤起始（“癌症干细胞”）特性的癌细胞子集。
Recent evidence suggests that blockade of aberrant Hedgehog signaling can be exploited as a therapeutic strategy for pancreatic cancer. Our previous studies using the prototype Hedgehog small-molecule antagonist cyclopamine had shown the striking inhibition of systemic metastases on Hedgehog blockade in spontaneously metastatic orthotopic xenograft models. Cyclopamine is a natural compound with suboptimal pharmacokinetics, which impedes clinical translation. In the present study, a novel, orally bioavailable small-molecule Hedgehog inhibitor, IPI-269609, was tested using in vitro and in vivo model systems. In vitro treatment of pancreatic cancer cell lines with IPI-269609 resembled effects observed using cyclopamine (i.e., Gli-responsive reporter knock-down, down-regulation of the Hedgehog target genes Gli1 and Ptch, as well as abrogation of cell migration and colony formation in soft agar). Single-agent IPI-269609 profoundly inhibited systemic metastases in orthotopic xenografts established from human pancreatic cancer cell lines, although Hedgehog blockade had minimal effect on primary tumor volume. The only discernible phenotype observed within the treated primary tumor was a significant reduction in the population of aldehyde dehydrogenase–bright cells, which we have previously identified as a clonogenic tumor-initiating population in pancreatic cancer. Selective ex vivo depletion of aldehyde dehydrogenase–bright cells with IPI-269609 was accompanied by significant reduction in tumor engraftment rates in athymic mice. Pharmacologic blockade of aberrant Hedgehog signaling might prove to be an effective therapeutic strategy for inhibition of systemic metastases in pancreatic cancer, likely through targeting subsets of cancer cells with tumor-initiating (“cancer stem cell”) properties.