Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer

Kenneth P. Olive; Michael A. Jacobetz; Christian J. Davidson; Aarthi Gopinathan; Dominick McIntyre; Davina Honess; Basetti Madhu; Mae A. Goldgraben; Meredith E. Caldwell; David Allard; Kristopher K. Frese; Gina DeNicola; Christine Feig; Chelsea Combs; Stephen P. Winter; Heather Ireland-Zecchini; Stefanie Reichelt; William J. Howat; Alex Chang; Mousumi Dhara; Lifu Wang; Felix Rückert; Robert Grützmann; Christian Pilarsky; Kamel Izeradjene; Sunil R. Hingorani; Pearl Huang; Susan E. Davies; William Plunkett; Merrill Egorin; Ralph H. Hruban; Nigel Whitebread; Karen McGovern; Julian Adams; Christine Iacobuzio-Donahue; John Griffiths; David A. Tuveson

doi:10.1126/science.1171362

Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer

Kenneth P. Olive, Michael A. Jacobetz, Christian J. Davidson, Aarthi Gopinathan, Dominick McIntyre, Davina Honess, Basetti Madhu, Mae A. Goldgraben, Meredith E. Caldwell, David Allard, Kristopher K. Frese, Gina DeNicola, Christine Feig, Chelsea Combs, Stephen P. Winter, Heather Ireland-Zecchini, Stefanie Reichelt, William J. Howat, Alex Chang, Mousumi DharaLifu Wang, Felix Rückert, Robert Grützmann, Christian Pilarsky, Kamel Izeradjene, Sunil R. Hingorani, Pearl Huang, Susan E. Davies, William Plunkett, Merrill Egorin, Ralph H. Hruban, Nigel Whitebread, Karen McGovern, Julian Adams, Christine Iacobuzio-Donahue, John Griffiths, David A. Tuveson

School of Medicine

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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.

Original language	English (US)
Pages (from-to)	1457-1461
Number of pages	5
Journal	Science
Volume	324
Issue number	5933
DOIs	https://doi.org/10.1126/science.1171362
State	Published - Jun 12 2009

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Olive, K. P., Jacobetz, M. A., Davidson, C. J., Gopinathan, A., McIntyre, D., Honess, D., Madhu, B., Goldgraben, M. A., Caldwell, M. E., Allard, D., Frese, K. K., DeNicola, G., Feig, C., Combs, C., Winter, S. P., Ireland-Zecchini, H., Reichelt, S., Howat, W. J., Chang, A., ... Tuveson, D. A. (2009). Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science, 324(5933), 1457-1461. https://doi.org/10.1126/science.1171362

Olive, KP, Jacobetz, MA, Davidson, CJ, Gopinathan, A, McIntyre, D, Honess, D, Madhu, B, Goldgraben, MA, Caldwell, ME, Allard, D, Frese, KK, DeNicola, G, Feig, C, Combs, C, Winter, SP, Ireland-Zecchini, H, Reichelt, S, Howat, WJ, Chang, A, Dhara, M, Wang, L, Rückert, F, Grützmann, R, Pilarsky, C, Izeradjene, K, Hingorani, SR, Huang, P, Davies, SE, Plunkett, W, Egorin, M, Hruban, RH, Whitebread, N, McGovern, K, Adams, J, Iacobuzio-Donahue, C, Griffiths, J & Tuveson, DA 2009, 'Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer', Science, vol. 324, no. 5933, pp. 1457-1461. https://doi.org/10.1126/science.1171362

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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.",

author = "Olive, {Kenneth P.} and Jacobetz, {Michael A.} and Davidson, {Christian J.} and Aarthi Gopinathan and Dominick McIntyre and Davina Honess and Basetti Madhu and Goldgraben, {Mae A.} and Caldwell, {Meredith E.} and David Allard and Frese, {Kristopher K.} and Gina DeNicola and Christine Feig and Chelsea Combs and Winter, {Stephen P.} and Heather Ireland-Zecchini and Stefanie Reichelt and Howat, {William J.} and Alex Chang and Mousumi Dhara and Lifu Wang and Felix R{\"u}ckert and Robert Gr{\"u}tzmann and Christian Pilarsky and Kamel Izeradjene and Hingorani, {Sunil R.} and Pearl Huang and Davies, {Susan E.} and William Plunkett and Merrill Egorin and Hruban, {Ralph H.} and Nigel Whitebread and Karen McGovern and Julian Adams and Christine Iacobuzio-Donahue and John Griffiths and Tuveson, {David A.}",

year = "2009",

month = jun,

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doi = "10.1126/science.1171362",

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AU - Olive, Kenneth P.

AU - Jacobetz, Michael A.

AU - Davidson, Christian J.

AU - Gopinathan, Aarthi

AU - McIntyre, Dominick

AU - Honess, Davina

AU - Madhu, Basetti

AU - Goldgraben, Mae A.

AU - Caldwell, Meredith E.

AU - Allard, David

AU - Frese, Kristopher K.

AU - DeNicola, Gina

AU - Feig, Christine

AU - Combs, Chelsea

AU - Winter, Stephen P.

AU - Ireland-Zecchini, Heather

AU - Reichelt, Stefanie

AU - Howat, William J.

AU - Chang, Alex

AU - Dhara, Mousumi

AU - Wang, Lifu

AU - Rückert, Felix

AU - Grützmann, Robert

AU - Pilarsky, Christian

AU - Izeradjene, Kamel

AU - Hingorani, Sunil R.

AU - Huang, Pearl

AU - Davies, Susan E.

AU - Plunkett, William

AU - Egorin, Merrill

AU - Hruban, Ralph H.

AU - Whitebread, Nigel

AU - McGovern, Karen

AU - Adams, Julian

AU - Iacobuzio-Donahue, Christine

AU - Griffiths, John

AU - Tuveson, David A.

PY - 2009/6/12

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N2 - 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.

AB - 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.

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Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer

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