title: Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer.
abstract: Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers in part because it is insensitive to many chemotherapeutic drugs. Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, we found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA. We tested whether the delivery and efficacy of gemcitabine in the mice could be improved by coadministration of IPI-926, a drug that depletes tumor-associated stromal tissue by inhibition of the Hedgehog cellular signaling pathway. The combination therapy produced a transient increase in intratumoral vascular density and intratumoral concentration of gemcitabine, leading to transient stabilization of disease. Thus, inefficient drug delivery may be an important contributor to chemoresistance in pancreatic cancer.
authors.affiliation: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 ORE, UK.
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Olive
authors.forename: Michael A
authors.initials: MA
authors.lastname: Jacobetz
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Davidson
authors.forename: Aarthi
authors.initials: A
authors.lastname: Gopinathan
authors.forename: Dominick
authors.initials: D
authors.lastname: McIntyre
authors.forename: Davina
authors.initials: D
authors.lastname: Honess
authors.forename: Basetti
authors.initials: B
authors.lastname: Madhu
authors.forename: Mae A
authors.initials: MA
authors.lastname: Goldgraben
authors.forename: Meredith E
authors.initials: ME
authors.lastname: Caldwell
authors.forename: David
authors.initials: D
authors.lastname: Allard
authors.forename: Kristopher K
authors.initials: KK
authors.lastname: Frese
authors.forename: Gina
authors.initials: G
authors.lastname: Denicola
authors.forename: Christine
authors.initials: C
authors.lastname: Feig
authors.forename: Chelsea
authors.initials: C
authors.lastname: Combs
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Winter
authors.forename: Heather
authors.initials: H
authors.lastname: Ireland-Zecchini
authors.forename: Stefanie
authors.initials: S
authors.lastname: Reichelt
authors.forename: William J
authors.initials: WJ
authors.lastname: Howat
authors.forename: Alex
authors.initials: A
authors.lastname: Chang
authors.forename: Mousumi
authors.initials: M
authors.lastname: Dhara
authors.forename: Lifu
authors.initials: L
authors.lastname: Wang
authors.forename: Felix
authors.initials: F
authors.lastname: Rückert
authors.forename: Robert
authors.initials: R
authors.lastname: Grützmann
authors.forename: Christian
authors.initials: C
authors.lastname: Pilarsky
authors.forename: Kamel
authors.initials: K
authors.lastname: Izeradjene
authors.forename: Sunil R
authors.initials: SR
authors.lastname: Hingorani
authors.forename: Pearl
authors.initials: P
authors.lastname: Huang
authors.forename: Susan E
authors.initials: SE
authors.lastname: Davies
authors.forename: William
authors.initials: W
authors.lastname: Plunkett
authors.forename: Merrill
authors.initials: M
authors.lastname: Egorin
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.forename: Nigel
authors.initials: N
authors.lastname: Whitebread
authors.forename: Karen
authors.initials: K
authors.lastname: McGovern
authors.forename: Julian
authors.initials: J
authors.lastname: Adams
authors.forename: Christine
authors.initials: C
authors.lastname: Iacobuzio-Donahue
authors.forename: John
authors.initials: J
authors.lastname: Griffiths
authors.forename: David A
authors.initials: DA
authors.lastname: Tuveson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000072086:Smoothened Receptor; D017154:Stromal Cells / Q000187:drug effects / Q000473:pathology; D014704:Veratrum Alkaloids / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000071676:Zinc Finger Protein GLI1; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; C541444:IPI-926; D051741:Kruppel-Like Transcription Factors; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; D003841:Deoxycytidine; D000093542:Gemcitabine