Hedghehog Related pancreatic articles (scientific) also more info here about pancreatic cancer
http://www.pathway2curis.com/pancreatic-cancer-hedgehog-vt22.html

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Abstract: DESCRIPTION (provided by applicant): Pancreatic cancer is a uniformly lethal disease, and there is an urgent need for potent, mechanism-based therapies to improve survival, especially in patients with metastatic, inoperable tumors. Hedgehog (Hh) pathway activation is seen in the majority of pancreatic cancer cell lines, and in vitro growth can be profoundly inhibited by the Hh small molecule antagonist cyclopamine. A comprehensive preclinical analysis of Hh inhibitors in pancreatic cancer is proposed, using in vivo models that recapitulate the complexities of human pancreatic cancer progression. Low-passage cell lines have been established from resected human pancreatic cancers, and will be used for generating orthotropic xenografts in pancreata of athymic mice. Either cyclopamine or an orally bioavailable synthetic Hh inhibitor (Genentech, Inc.) will be administered as monotherapy for 28 days. Treatment efficacy versus control mice will be assessed at necropsy by objective gross and histopathologic parameters, including development of intra-abdominal metastases, and by survival analysis. Synergism between the Hh antagonists and an anti-metabolite (gemcitabine) will be assessed in a subset of xenografted cancers. A transgenic mouse model of pancreatic intraepithelial neoplasia and invasive pancreatic cancer has been developed by misexpression of oncogenic KRAS in the pancreas. The role of Hh signaling, including effects of inhibiting pathway during the multistage progression to invasive cancer, will be studied in this model. As a prelude to clinical trials, biomarkers that predict responsiveness to Hh antagonists will be defined by correlating in vitro therapeutic response with the expression of Hh pathway genes and to global expression profiles determined using oligonucleotide microarrays, in a panel of 50 pancreatic cancer cell lines. Based on the efficacy of Hh inhibitors in the preclinical studies and the identification of predictive biomarkers for response, Phase II clinical trials will be initiated in patients with unresectable pancreatic cancers using the orally bioavailable synthetic Hh inhibitors.

Pancreas. 2006 Mar;32(2):119-29. Links

Hedgehog signaling in the normal and diseased pancreas.

Kayed H, Kleeff J, Osman T, Keleg S, Buchler MW, Friess H.

Department of General Surgery, University of Heidelberg, Heidelberg, Germany.

The hedgehog (Hh) family of genes, sonic hedgehog (Shh), Indian hedgehog (Ihh), and desert hedgehog (Dhh) encode signaling molecules that regulate multiple functions during organ development and in adult tissues. Altered hedgehog signaling has been implicated in disturbed organ development as well as in different degenerative and neoplastic human diseases. Hedgehog signaling plays an important role in determination the fate of the mesoderm of the gut tube, as well as in early pancreatic development, and islet cell function. Recently, it has been shown that deregulation of hedgehog signaling molecules contributes to the pathogenesis and progression of pancreatic cancer and of chronic pancreatitis. Inhibition of hedgehog signaling using hedgehog antagonists reduces pancreatic cancer cell growth in vitro and in vivo, thus holding promise of novel agents in the treatment of this devastating disease. In this review, we discuss the role of hedgehog signaling during pancreatic development, its role in the pathogenesis of both chronic pancreatitis and pancreatic cancer, and lastly, the implications of this newly available information with regards to treatment of pancreatic cancer.

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Cancer Chemother Pharmacol. 2006 Mar 22; [Epub ahead of print] Links

Cyclopamine increases the cytotoxic effects of paclitaxel and radiation but not cisplatin and gemcitabine in Hedgehog expressing pancreatic cancer cells.

Shafaee Z, Schmidt H, Du W, Posner M, Weichselbaum R.

Department of Surgery, University of Chicago, S. Maryland Avenue, 5841, Chicago, IL, 60637, USA, pschmidt@surgery.bsd.uchicago.edu.

Introduction: The hedgehog signaling pathway (Hh) is frequently over expressed in pancreatic adenocarcinomas. We studied the potential cytotoxic interactions between cyclopamine, a Hh pathway inhibitor and paclitaxel, cisplatin, gemcitabine and ionizing radiation (IR). Methods: In vitro clonogenic survival analysis was performed with cyclopamine alone or cyclopamine in combination with paclitaxel, gemcitabine, cisplatin and IR in Hh expressing human pancreatic tumor cells and Hh non-expressing colon cancer cells. Relative cytotoxicity was assessed in combination treatment compared with exposure to single agents. Assays of apoptosis (annexin V) were performed in the presence of cyclopamine, chemotherapeutic agents, and IR. Results: We report that cyclopamine increased the cytotoxic effects of paclitaxel and IR in Hh expressing pancreatic carcinoma cells. These effects were not observed in Hh non-expressing cells. Cyclopamine did not significantly increase killing by cisplatin or gemcitabine in Hh expressing pancreatic cancer cells. Conclusions: These data suggest strategies to combine Hh inhibitors with radiotherapy and chemotherapeutic agents, specifically paclitaxel and related compounds in the treatment of pancreatic cancer.
"In summary our data suggest that cyclopamine is a
potentially useful agent to improve results in pancreatic
cancer when combined with paclitaxel or radiation therapy.
We speculate that paclitaxel and cyclopamine, compared
with radiation and cyclopamine, interact through
diVerent pathways since an increase in tumor cell apoptosis
mediates some of the interactive cytotoxic eVects
with paclitaxel and cyclopamine, but not radiation and
cyclopamine."

"Paclitaxel is a cytotoxic agent that stabilizes microtubules.
Although no data is available regarding eVects of
cyclopamine on the microtubule cytoskeleton, several
reports have described putative roles for the Hedgehog
pathway in this compartment."



So not only do you stop the Smo from being active you break the road way for Gli to get into the cell and activate target genes.
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Cell Mol Life Sci. 2006 Feb 7; [Epub ahead of print]

Hedgehog signaling in pancreas development and disease.

Lau J, Kawahira H, Hebrok M.

Diabetes Center and Department of Medicine, University of California, San Francisco, 513 Parnassus Ave., San Francisco, California, 94143, USA, mhebrok@diabetes.ucsf.edu.

Since its discovery, numerous studies have shown that the Hedgehog (Hh) signaling pathway plays an instrumental role during diverse processes of cell differentiation and organ development. More recently, it has become evident that Hh signaling is not restricted to developmental events, but retains some of its activity during adult life. In mature tissues, Hh signaling has been implicated in the maintenance of stem cell niches in the brain, renewal of the gut epithelium and differentiation of hematopoietic cells. In addition to the basal function in adult tissue, deregulated signaling has been implicated in a variety of cancers, including basal cell carcinoma, glioma and small cell lung cancer. Here, we will focus on the role of Hh signaling in pancreas development and pancreatic diseases, including diabetes mellitus, chronic pancreatitis and pancreatic cancer.

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