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Published on: January 4, 2012
Targeting eNOS in pancreatic cancer
Benjamin L Lampson1, S Disean Kendall, Brooke B Ancrile
1Departments of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.
Abstract:
Mortality from pancreatic ductal adenocarcinoma cancer (PDAC) is among the highest of any cancer and frontline therapy has changed little in years. Activation of endothelial nitric oxide synthase (eNOS, NOS3, or NOS III) has been implicated recently in the pathogenesis of PDACs. In this study, we used genetically engineered mouse and human xenograft models to evaluate the consequences of targeting eNOS in PDACs. Genetic deficiency in eNOS limited the development of preinvasive pancreatic lesions and trended toward an extended lifespan in mice with advanced pancreatic cancer. These effects were also observed upon oral administration of the clinically evaluated NOS small molecule inhibitor N(G)-nitro-L-arginine methyl ester (l-NAME). Similarly, other transgenic models of oncogenic KRas-driven tumors responded to l-NAME treatment. Finally, these results were recapitulated in xenograft models of human pancreatic cancer, in which l-NAME was found to broadly inhibit tumorigenic growth. Taken together, our findings offer preclinical proof-of-principle to repurpose l-NAME for clinical investigations in treatment of PDACs and possibly other KRas-driven human cancers.
Insights
Targeting endothelial nitric oxide synthase (eNOS) shows promise for pancreatic cancer treatment. Inhibiting eNOS with l-NAME slowed tumor growth and extended lifespan in preclinical models, suggesting repurposing for PDAC therapy.
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) has high mortality with limited therapeutic advancements.
- Endothelial nitric oxide synthase (eNOS) activation is increasingly implicated in PDAC development and progression.
Purpose of the Study:
- To investigate the therapeutic potential of targeting eNOS in PDAC.
- To evaluate the efficacy of eNOS inhibition in preclinical models of pancreatic cancer.
Main Methods:
- Utilized genetically engineered mouse models and human xenograft models of PDAC.
- Assessed the impact of genetic eNOS deficiency and pharmacological inhibition with l-NAME.
- Examined effects on preinvasive lesions, tumor growth, and lifespan.
Main Results:
- Genetic eNOS deficiency limited preinvasive lesion development and extended survival in advanced PDAC mouse models.
- Oral administration of l-NAME, a clinically evaluated NOS inhibitor, replicated these beneficial effects.
- l-NAME treatment inhibited tumor growth in various oncogenic KRas-driven tumor models and human pancreatic cancer xenografts.
Conclusions:
- Findings provide preclinical evidence supporting the repurposing of l-NAME for PDAC treatment.
- eNOS inhibition represents a potential therapeutic strategy for PDAC and other KRas-driven cancers.
