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PDF file - 372K, Supplementary Figure 1 (Fig.S1)- Detection of CD24 transcript in AsPC1 cells, Supplementary Figure 2 (Fig.S2) Detection of Hh target genes in orthotopic pancreatic cancer models, Supplementary Figure 3 (Fig.S3) Expression of SHH and IHH in AsPC1-derived tumors, Supplementary Figure 4 (Fig.S4) Expression of mouse Hh target genes in AsPC1- and MIA PaCa2-derived tumors, Supplementary Figure 5 (Fig.S5) Picture of tumor spheres (100X) from AsPC1-derived pancreatic tumors or lymph node metastases, Supplementary Figure 6 (Fig.S6) Effect of CycT on tumor sphere regeneration, Supplementary Figure 7 (Fig.S7) Effects of combining radiation with Hh signaling inhibition on tumor sphere regeneration of MMC16 cells, Supplementary Figure 8 (Fig.S8) Effects of Hh signaling inhibitor BMS833923 on Hh target gene expression in AsPC1 derived orthotopic model, Supplementary Figure 9 (Fig.S9) Effects of irradiation and Hh signaling inhibitor BMS (BMS833932) on lung metastasis, Supplementary Figure 10 (Fig.S10) Regulation of putative Hh target genes by Hh signaling inhibition in pancreatic cancer

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Pancreatic cancer often presents in advanced stages and is unresponsive to conventional treatments. Thus, the need to develop novel treatment strategies for pancreatic cancer has never been greater. Here, we report that combination of focal irradiation with hedgehog (Hh) signaling inhibition exerts better than additive effects on reducing metastases. In an orthotopic model, we found that focal irradiation alone effectively reduced primary tumor growth but did not significantly affect metastasis. We hypothesized that cancer stem cells (CSC) of pancreatic cancer are responsible for the residual tumors following irradiation, which may be regulated by Hh signaling. To test our hypothesis, we showed that tumor metastasis in our model was accompanied by increased expression of CSC cell surface markers as well as Hh target genes. We generated tumor spheres from orthotopic pancreatic and metastatic tumors, which have elevated levels of CSC markers relative to the parental cells and elevated expression of Hh target genes. Irradiation of tumor spheres further elevated CSC cell surface markers and increased Hh target gene expression. Combination of Hh signaling inhibition with radiation had more than additive effects on tumor sphere regeneration in vitro. This phenotype was observed in two independent cell lines. In our orthotopic animal model, focal radiation plus Hh inhibition had more than additive effects on reducing lymph node metastasis. We identified several potential molecules in mediating Hh signaling effects. Taken together, our data provide a rationale for combined use of Hh inhibition with irradiation for clinical treatment of patients with pancreatic cancer. Mol Cancer Ther; 12(6); 1038–48. ©2013 AACR.

Treatment induced secondary malignancies after successful radiation and/or chemotherapy cure of primary tumors is a growing area of concern. The identification of chemopreventive compounds that reduce radiation-induced secondary malignancy but are both nontoxic and tolerated with long-term use is a critical need. We investigated the chemopreventive potential and mechanism of action of Vitamin E and EGCG (the active agent in green tea) with the human CGL1 radiation neoplastic transformation assay. The molecularly characterized CGL1 assay allows both alterations of the quantitative neoplastic transformation as well the potential underlying molecular processes of the chemoprevention to be determined. We found long-term treatment with 15 microM EGCG or 50 microM Vitamin E beginning 72 hours after 7 Gy irradiation, significantly reduce radiation-induced neoplastic transformation frequency by a factor of 2.3. We determined that Vit E suppressed radiation-induced carcinogenesis by the induction of a p53 and pro-apoptotic Bax dependent apoptosis in the progeny of the irradiated cells. In addition, we demonstrated that EGCG does not reduce radiation-induced carcinogenesis by increased apoptosis, but rather by the onset of p16 dependent senescence in the irradiated CGL1 progeny. Vit E and EGCG are excellent candidate nontoxic chemopreventive agents for radiation-induced carcinogenesis that work by two distinct molecular mechanisms. We propose that this information should also aid in the development of next generation chemopreventive compounds. These studies were supported by a grant from the DOD awarded to MSM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4368.