Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer
Kenneth P. Olive,Michael A. Jacobetz,Christian Davidson,Aarthi Gopinathan,Aarthi Gopinathan,Dominick J.O. McIntyre,Davina J. Honess,Basetti Madhu,Mae A. Goldgraben,Meredith E. Caldwell,David Allard,Kristopher K. Frese,Gina M. DeNicola,Gina M. DeNicola,Christine Feig,Chelsea Combs,Stephen P. Winter,Heather Ireland-Zecchini,Stefanie Reichelt,William J. Howat,Alex R. Chang,Mousumi Dhara,Lifu Wang,Lifu Wang,Felix Rückert,Robert Grützmann,Christian Pilarsky,Kamel Izeradjene,Sunil R. Hingorani,Pearl S. Huang,Susan E. Davies,William Plunkett,Merrill J. Egorin,Ralph H. Hruban,Nigel Whitebread,Karen McGovern,Julian Adams,Christine A. Iacobuzio-Donahue,John R. Griffiths,David A. Tuveson +39 more
TLDR
Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, it is found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA.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.read more
Citations
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References
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Journal ArticleDOI
Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial.
H. A. Burris,Malcolm J. Moore,J. S. Andersen,M R Green,Mace L. Rothenberg,M R Modiano,M. C. Cripps,Russell K. Portenoy,A M Storniolo,P Tarassoff,R Nelson,F A Dorr,C. D. Stephens,D. D. Von Hoff +13 more
TL;DR: It is demonstrated that gemcitabine is more effective than 5-FU in alleviation of some disease-related symptoms in patients with advanced, symptomatic pancreas cancer and confers a modest survival advantage over treatment with5-FU.
Journal ArticleDOI
Drug penetration in solid tumours
TL;DR: The evidence that indicates that the distribution of many anticancer drugs in tumours is incomplete is summarized, and strategies that might be used either to improve drug penetration through tumour tissue or to select compounds based on their abilities to penetrate tissue are suggested, thereby increasing the therapeutic index.
Journal ArticleDOI
Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice
Sunil R. Hingorani,Lifu Wang,Asha S. Multani,Chelsea Combs,Therese B. Deramaudt,Ralph H. Hruban,Anil K. Rustgi,Sandy Chang,David A. Tuveson +8 more
TL;DR: Targeted concomitant endogenous expression of Trp53(R172H) and Kras(G12D) to the mouse pancreas reveals the cooperative development of invasive and widely metastatic carcinoma that recapitulates the human disease.
Journal ArticleDOI
Drug Resistance and the Solid Tumor Microenvironment
TL;DR: How the tumor microenvironment may be involved in the resistance of solid tumors to chemotherapy and potential strategies to improve the effectiveness of drug treatment by modifying factors relating to the tumormicroenvironment are described.
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