title: An orally bioavailable small-molecule inhibitor of Hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancer.
abstract: 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 knockdown, 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.
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, CRB2, Room 316, 1550 Orleans Street, Baltimore, MD 21231, USA. gfeldma4@jhmi.edu
authors.forename: Georg
authors.initials: G
authors.lastname: Feldmann
authors.forename: Volker
authors.initials: V
authors.lastname: Fendrich
authors.forename: Karen
authors.initials: K
authors.lastname: McGovern
authors.forename: Djahida
authors.initials: D
authors.lastname: Bedja
authors.forename: Savita
authors.initials: S
authors.lastname: Bisht
authors.forename: Hector
authors.initials: H
authors.lastname: Alvarez
authors.forename: Jan-Bart M
authors.initials: JB
authors.lastname: Koorstra
authors.forename: Nils
authors.initials: N
authors.lastname: Habbe
authors.forename: Collins
authors.initials: C
authors.lastname: Karikari
authors.forename: Michael
authors.initials: M
authors.lastname: Mullendore
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Gabrielson
authors.forename: Rajni
authors.initials: R
authors.lastname: Sharma
authors.forename: William
authors.initials: W
authors.lastname: Matsui
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D052176:Azulenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D052176:Azulenes; D019086:Bridged Bicyclo Compounds, Heterocyclic; D053823:Hedgehog Proteins; C532361:IPI 269609; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface
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