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 inhibiting the † To whom correspondence should be addressed. david.tuveson@cancer.org.uk.

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

“…Several studies have shown that Hh-signaling activation is associated with chemotherapy resistance or radiotherapy resistance (Sims-Mourtada et al, 2006;Yoshikawa et al, 2008;Olive et al, 2009), supporting that hedgehog signaling activation has a role in cancer stem cell functions. It was recently reported that Hh-signaling inhibitor enhances the delivery of chemotherapy in a mouse model of pancreatic cancer (Olive et al, 2009). Despite all these progresses, more experiments are needed to determine whether Hh signaling is important for cancer stem cells in solid tumors.…”

“…Based on cancer stem cell theory, one would anticipate that Hh-signaling activation may exert chemotherapy or radiotherapy resistance in cancer if this pathway has a major role in cancer stem cell functions (Reya et al, 2001). Several studies have shown that Hh-signaling activation is associated with chemotherapy resistance or radiotherapy resistance (Sims-Mourtada et al, 2006;Yoshikawa et al, 2008;Olive et al, 2009), supporting that hedgehog signaling activation has a role in cancer stem cell functions. It was recently reported that Hh-signaling inhibitor enhances the delivery of chemotherapy in a mouse model of pancreatic cancer (Olive et al, 2009).…”

Friendly neighbours feed tumour cells

“…As well as the tumour cells, desmoplasia involves other cell types, including pancreatic stellate cells, which are mainly responsible for the condition, and immune cells. Desmoplasia is a serious medical concern, because it forms a barrier to treatment with chemotherapeutic drugs as a result of poor blood perfusion into the tumour 5 . Paradoxically, desmoplasia is promoted by the release of signalling factors by the tumour, even though it also impedes the tumour's blood supply and hence its access to oxygen, glucose and other nutrients.…”

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

“…These features are not recapitulated by subcutaneously growing PDACs, which lack the abundant desmoplastic stroma and high interstitial pressure that limits blood vessel functionality in autochthonous (or orthotopic) tumors. Even orthotopic xenotransplant PDAC tumors growing in the pancreas are hypervascular in comparison to genetically engineered mouse models (GEMMs) and human PDACs (Olive et al., 2009); for other tumor types, however, orthotopic transplants may more accurately reflect the bona fide angiogenic and stromal components of the tumor microenvironment, and as such present an important experimental alternative to subcutaneous tumor xenografts (Francia et al., 2011). …”