Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer by Olive Kenneth P, Jacobetz Michael A, Davidson Christian J, Gopinathan Aarthi, McIntyre Dominick, Honess Davina, Madhu Basetti, Goldgraben Mae A, Caldwell Meredith E, Allard David, Frese Kristopher K, Denicola Gina, Feig Christine, Combs Chelsea, Winter Stephen P, Ireland-Zecchini Heather, Reichelt Stefanie, Howat William J, Chang Alex, Dhara Mousumi, Wang Lifu, Rückert Felix, Grützmann Robert, Pilarsky Christian, Izeradjene Kamel, Hingorani Sunil R, Huang Pearl, Davies Susan E, Plunkett William, Egorin Merrill, Hruban Ralph H, Whitebread Nigel, McGovern Karen, Adams Julian, Iacobuzio-Donahue Christine, Griffiths John, Tuveson David A in Science (New York, N.Y.) (2009). PubMed

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.

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