Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer

By K. Olive, Michael A. Jacobetz, Christian J Davidson, A. Gopinathan, D. McIntyre, D. Honess, B. Madhu, M. Goldgraben, Meredith E. Caldwell, D. Allard and 27 more. Science, 2009

3,151 citations recorded by the source corpus.

It's All in the Delivery Pancreatic cancer is almost universally associated with a poor prognosis, in part because the tumors are resistant to chemotherapeutic drugs. Working with a mouse tumor model that displays many features of the human disease, Olive et al. (p. 1457, published online 21 May; see the Perspective by Olson and Hanahan) found that the tumors were poorly vascularized, a factor likely to impede drug delivery. Treatment of the mice with the chemotherapeutic drug gemcitabine in combination with a drug that depletes tumor-associated stromal tissue led to an increase in tumor vasculature, enhanced delivery of gemcitabine, and a delay in disease progression. Thus, drugs targeting the tumor stroma may merit investigation as a way to enhance the efficacy of conventional chemotherapy for pancreatic cancer. Pancreatic tumors are unresponsive to chemotherapy because their limited vasculature precludes efficient drug delivery. 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.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/499470b95ff9332e5dd22c8c122fde007eb28703

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Citations in the corpus

Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions (2014, background): “This might be particularly pertinent in poorly vascularised cancers such as pancreatic adenocarcinoma where improved delivery of chemotherapy could be beneficial [250].”
Extracellular matrix: a dynamic niche component during cancer progression (2012, positive): “Indeed, a decrease in the fibroblast pool and thus the ECM improves drug uptake in the mouse (Loeffler et al., 2006; Olive et al., 2009).”
Recent progress in pancreatic cancer (2013, background): “The desmoplastic reaction associated with pancreatic cancer has to be taken into account when designing therapeutic regimens, because even the best agents will not be effective if they do not reach the neoplastic cells.(57) Some have also suggested that the desmoplastic reaction can be exploited the”
Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma (2012, methodology): “In previous studies of gemcitabine in KPC mice (Olive et al., 2009), we used a dose, route, and schedule modeled on the original preclinical investigations of gemcitabine in subcutaneously engrafted tumors (Hertel et al., 1990; Schultz et al., 1993).”