Department of Vincent Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
PLoS One. 2011;6(11):e28077. doi: 10.1371/journal.pone.0028077. Epub 2011 Nov 29.
Recent evidence links aberrant activation of Hedgehog (Hh) signaling with the pathogenesis of several cancers including medulloblastoma, basal cell, small cell lung, pancreatic, prostate and ovarian. This investigation was designed to determine if inhibition of this pathway could inhibit serous ovarian cancer growth.
We utilized an in vivo pre-clinical model of serous ovarian cancer to characterize the anti-tumor activity of Hh pathway inhibitors cyclopamine and a clinically applicable derivative, IPI-926. Primary human serous ovarian tumor tissue was used to generate tumor xenografts in mice that were subsequently treated with cyclopamine or IPI-926.
Both compounds demonstrated significant anti-tumor activity as single agents. When IPI-926 was used in combination with paclitaxel and carboplatinum (T/C), no synergistic effect was observed, though sustained treatment with IPI-926 after cessation of T/C continued to suppress tumor growth. Hh pathway activity was analyzed by RT-PCR to assess changes in Gli1 transcript levels. A single dose of IPI-926 inhibited mouse stromal Gli1 transcript levels at 24 hours with unchanged human intra-tumor Gli1 levels. Chronic IPI-926 therapy for 21 days, however, inhibited Hh signaling in both mouse stromal and human tumor cells. Expression data from the micro-dissected stroma in human serous ovarian tumors confirmed the presence of Gli1 transcript and a significant association between elevated Gli1 transcript levels and worsened survival.
CONCLUSIONS/SIGNIFICANCE: IPI-926 treatment inhibits serous tumor growth suggesting the Hh signaling pathway contributes to the pathogenesis of ovarian cancer and may hold promise as a novel therapeutic target, especially in the maintenance setting.
最近的证据表明 Hedgehog（Hh）信号通路的异常激活与几种癌症的发病机制有关，包括髓母细胞瘤、基底细胞癌、小细胞肺癌、胰腺癌、前列腺癌和卵巢癌。本研究旨在确定抑制该通路是否能抑制浆液性卵巢癌的生长。
我们利用浆液性卵巢癌的体内临床前模型，来研究 Hh 通路抑制剂环巴胺和一种临床适用的衍生物 IPI-926 的抗肿瘤活性。我们使用原发性人浆液性卵巢肿瘤组织在小鼠中生成肿瘤异种移植物，然后用环巴胺或 IPI-926 进行治疗。
这两种化合物作为单一药物都具有显著的抗肿瘤活性。当 IPI-926 与紫杉醇和卡铂（T/C）联合使用时，没有观察到协同作用，尽管在停止 T/C 后持续使用 IPI-926 仍能抑制肿瘤生长。通过 RT-PCR 分析 Hh 通路活性，以评估 Gli1 转录本水平的变化。单次给予 IPI-926 可在 24 小时内抑制小鼠基质 Gli1 转录本水平，但不改变人肿瘤内 Gli1 水平。然而，连续 21 天给予 IPI-926 治疗可抑制小鼠基质和人肿瘤细胞中的 Hh 信号通路。从人浆液性卵巢肿瘤的微切割基质获得的表达数据证实了 Gli1 转录本的存在，以及升高的 Gli1 转录本水平与生存恶化之间存在显著相关性。
结论/意义：IPI-926 治疗抑制浆液性肿瘤生长，表明 Hh 信号通路参与卵巢癌的发病机制，并且可能作为一种新的治疗靶点具有潜力，特别是在维持治疗中。
