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More on Pancreatic

2011 Jan 5

Rationale for Inhibition of the Hedgehog Pathway Paracrine Loop in Pancreatic Adenocarcinoma

hedgehog pathway contributes to the molecular conversation between tumor and its microenvironment through a (paracrine loop)

Olive et al. [32] provided evidence that chemotherapy does not have access to the tumor cells in KRAS and p53 mutant pancreatic adenocarcinoma xenografts in a gemcitabine resistant mouse model due to poor vascularization of the tumors. When combining gemcitabine with hedgehog inhibition (IPI-926, a specific SMO inhibitor) however, tumor vasculature and subsequently gemcitabine delivery in the tumors were enhanced. Mean vessel density and CD31 positive cells increased whereas stromal myofibroblasts were reduced. Mice treated with the combination had their tumors reduced in size, undergoing apoptosis and had significantly improved survival eventually. On the other hand, IPI-926 had no effect on cell proliferation in these KRAS driven tumors.

...implying the possible role of hedgehog inhibition in reducing the stem cell burden of the tumor that is responsible for resistance to therapy and recurrences

...Both studies concluded that the addition of hedgehog inhibition in chemotherapy specifically targets aldehyde dehydrogenase positive cells and reduces the number of metastases observed whereas it does not have significant effect on primary tumor volume.

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