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• W2335017796 abstract "Abstract Chondrosarcoma is a malignant cartilage tumor in which there is constitutive activation of Hedgehog-mediated signaling. Pharmacologic agents that inhibit Hedgehog (Hh) signaling have the potential to be used as novel targeted anti-tumor therapies. IPI-926, a novel, selective, molecule that antagonizes the Hh pathway by binding to Smoothened, is currently in clinical trials. The activity of IPI-926 was assessed in human primary chondrosarcoma tumors obtained at surgery from six different donors and grown as subcutaneous xenografts in NOD/SCID mice. Studies were conducted in primary chondrosarcoma xenografts to assess the activity of IPI-926 either at time of implant or in established tumors and to compare the anti-tumor activity of IPI-926 to chemotherapy and targeted agents. Tumor tissue was collected post-treatment at the end of each study for histopathological analysis or for evaluation of expression of Hh pathway genes by RT-PCR for GLI1, PTCH-1, and SMO mRNA. The chondrosarcoma tumor sizes were significantly smaller in the IPI-926 treated groups, compared to either control or chemotherapy-treated groups. There was also less cellularity, with cells appearing more differentiated, in the IPI-926 treated group. The tumors from mice treated with IPI-926 had significantly reduced expression of Hedgehog target genes GLI1 and PTCH1 compared to those from mice treated with vehicle or other chemotherapies. In addition, inhibition of GLI1 and PTCH1 gene expression was detected in the human tumor cells, a finding that has not been previously demonstrated in carcinomas, where the Hedgehog blockade seems to affect primarily the murine-derived stromal cells. As expected, inhibition of Hh target gene expression was also detected in the tumor stroma in these xenografts. Initial results from gene expression profiling of the tumor cells suggest that several additional genes may be affected by IPI-926 treatment. In summary, IPI-926 administration to mice bearing tumors derived from primary human chondrosarcoma tumors results in down-modulation of the Hh pathway in the tumor cells, as demonstrated by evaluation of the Hh-dependent genes GLI1 and PTCH1. Hh pathway gene expression is also inhibited in the tumor stroma. Down-modulation of the Hh pathway with IPI-926 results in inhibition of growth of both newly implanted and established chondrosarcoma tumors. Decreased tumor growth is accompanied by histopathological changes, including loss of cellularity and calcification. Thus, IPI-926 directly targets the Hh pathway in chondrosarcoma tumor cells and results in growth inhibition and changes in the tumor histopathology. These studies provide strong scientific rationale for further evaluation of Hh pathway inhibition with IPI-926 in humans with chondrosarcoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-380. doi:10.1158/1538-7445.AM2011-LB-380" @default.
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• W2335017796 date "2011-04-01" @default.
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• W2335017796 title "Abstract LB-380: Direct targeting of the Hedgehog pathway in primary chondrosarcoma xenografts with the Smoothened inhibitor IPI-926" @default.
• W2335017796 doi "https://doi.org/10.1158/1538-7445.am2011-lb-380" @default.
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