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Model Characteristics - Model:
Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer.
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| Model Descriptor |
Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer.
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| Official Nomenclature |
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| Genotype |
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| Species |
Mouse (Mus musculus)
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| Strain |
129
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| Is This a Tool Strain? |
No
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Developmental Stage
(applies only to Zebrafish) |
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| Experimental Design |
KPC mice harbor heterozygous conditional mutant alleles of Kras and p53 as well as a
pancreatic-specific Cre recombinase, Pdx1-Cre. Mice bearing the uK/uras, up/u53 and uC/ure alleles (KPC mice) develop a full spectrum of premalignant neoplasms that stochastically undergo loss of the remaining wild-type Trp53 allele and culminate in overt invasive and metastatic pancreatic ductal
adenocarcinoma (PDA) with a mean survival of 4.5 months. The KPC mice utilized in this paper
harbor one of two conditional point-mutant p53 alleles: p53supLSL-R172H/sup or p53supLSL-R270H/sup.
These two mutations have been reported to have largely similar functions in cells and in
mice. KrassupLSL-G12D/+/sup, p53supR172H/+/sup, Pdx1-Cre mice have been described, but
compound mutant mice with the latter allele, KrassupLSL-G12D/+/sup, Trpsup53LSL-R270H/+/sup, Pdx1-Cre, have not been previously reported. These mice develop advanced pancreatic ductal adenocarcinoma that appears similar to mice harboring the Trp53supR172H/sup allele.
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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.
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| Phenotype |
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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| Website for add. info |
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| Breeding Notes |
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| Sex Distribution of the Phenotype |
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| Submitted by |
caMOD, Curator
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| Principal Investigator / Lab |
Tuveson, David
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| Comment |
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| Model Availability: This model is available from |
| Strain |
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