Therapeutic Effects of an Anti-Myc Drug on Mouse Pancreatic Cancer

• Published in: JNCI : Journal of the National Cancer Institute 2014-12, Vol.106 (12), p.1
• Main Authors: STELLAS, Dimitris, SZABOLCS, Matthias, KOUL, Sanjay, ZHE LI, POLYZOS, Alexander, ANAGNOSTOPOULOS, Constantinos, COURNIA, Zoe, TAMVAKOPOULOS, Constantin, KLINAKIS, Apostolos, EFSTRATIADIS, Argiris
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Cell Proliferation - drug effects; Cells; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic; Gene Knock-In Techniques; Immunohistochemistry; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Medical treatment; Mice; Mice, Inbred NOD; Mice, SCID; Mice, Transgenic; Molecules; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Positron-Emission Tomography; Proto-Oncogene Proteins c-myc - antagonists & inhibitors; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins p21(ras) - genetics; Rodents; Thiazoles - pharmacology; Tomography, X-Ray Computed; Tumors; Up-Regulation; Xenograft Model Antitumor Assays
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/dju320

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. 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. 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). These results provide strong justification for eventual clinical evaluation of anti-Myc drugs as potential chemotherapeutic agents for the treatment of PDA.