Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer.
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.
Olive
Kenneth P
KP
Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 ORE, UK.
Jacobetz
Michael A
MA
Davidson
Christian J
CJ
Gopinathan
Aarthi
A
McIntyre
Dominick
D
Honess
Davina
D
Madhu
Basetti
B
Goldgraben
Mae A
MA
Caldwell
Meredith E
ME
Allard
David
D
Frese
Kristopher K
KK
Denicola
Gina
G
Feig
Christine
C
Combs
Chelsea
C
Winter
Stephen P
SP
Ireland-Zecchini
Heather
H
Reichelt
Stefanie
S
Howat
William J
WJ
Chang
Alex
A
Dhara
Mousumi
M
Wang
Lifu
L
Rückert
Felix
F
Grützmann
Robert
R
Pilarsky
Christian
C
Izeradjene
Kamel
K
Hingorani
Sunil R
SR
Huang
Pearl
P
Davies
Susan E
SE
Plunkett
William
W
Egorin
Merrill
M
Hruban
Ralph H
RH
Whitebread
Nigel
N
McGovern
Karen
K
Adams
Julian
J
Iacobuzio-Donahue
Christine
C
Griffiths
John
J
Tuveson
David A
DA
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
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