BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is frequently driven by 
oncogenic KRAS(KRAS*) mutations. We developed a mouse model of KRAS*-induced PDA 
and, based on genetic results demonstrating that KRAS* tumorigenicity depends on 
Myc activity, we evaluated the therapeutic potential of an orally administered 
anti-Myc drug.
METHODS: We tested the efficacy of Mycro3, a small-molecule inhibitor of Myc-Max 
dimerization, in the treatment of mouse PDA (n = 9) and also of xenografts of 
human pancreatic cancer cell lines (NOD/SCID mice, n = 3-12). Tumor responses to 
the drug were evaluated by PET/CT imaging, and histological, 
immunohistochemical, molecular and microarray analyses. The Student's t test was 
used for differences between groups. All statistical tests were two-sided.
RESULTS: Transgenic overexpression of KRAS* in the pancreas resulted in 
pancreatic intraepithelial neoplasia in two-week old mice, which developed 
invasive PDA a week later and became moribund at one month. However, this 
aggressive form of pancreatic tumorigenesis was effectively prevented by genetic 
ablation of Myc specifically in the pancreas. We then treated moribund, 
PDA-bearing mice daily with the Mycro3 Myc-inhibitor. The mice survived until 
killed at two months. PET/CT image analysis (n = 5) demonstrated marked 
shrinkage of PDA, while immunohistochemical analyses showed an increase in 
cancer cell apoptosis and reduction in cell proliferation (treated/untreated 
proliferation index ratio: 0.29, P < .001, n = 3, each group). Tumor growth was 
also drastically attenuated in Mycro3-treated NOD/SCID mice (n = 12) carrying 
orthotopic or heterotopic xenografts of human pancreatic cancer cells (eg, mean 
tumor weight ± SD of treated heterotopic xenografts vs vehicle-treated controls: 
15.2±5.8 mg vs 230.2±43.9 mg, P < .001).
CONCLUSION: These results provide strong justification for eventual clinical 
evaluation of anti-Myc drugs as potential chemotherapeutic agents for the 
treatment of PDA.