title: Therapeutic effects of an anti-Myc drug on mouse pancreatic cancer.
abstract: 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).
  
  
  CONCLUSIONS
  These results provide strong justification for eventual clinical evaluation of anti-Myc drugs as potential chemotherapeutic agents for the treatment of PDA.
authors.affiliation: Biomedical Research Foundation, Academy of Athens, Athens, Greece (DS, AP, CA, ZC, CT, AK, AE); Department of Pathology and Cell Biology (MS) and Division of Hematology/Oncology (SK), Columbia University Medical Center, New York, NY; Regeneron Research Laboratories, Tarrytown, NY (ZL).
authors.forename: Dimitris
authors.initials: D
authors.lastname: Stellas
authors.affiliation: Biomedical Research Foundation, Academy of Athens, Athens, Greece (DS, AP, CA, ZC, CT, AK, AE); Department of Pathology and Cell Biology (MS) and Division of Hematology/Oncology (SK), Columbia University Medical Center, New York, NY; Regeneron Research Laboratories, Tarrytown, NY (ZL).
authors.forename: Matthias
authors.initials: M
authors.lastname: Szabolcs
authors.affiliation: Biomedical Research Foundation, Academy of Athens, Athens, Greece (DS, AP, CA, ZC, CT, AK, AE); Department of Pathology and Cell Biology (MS) and Division of Hematology/Oncology (SK), Columbia University Medical Center, New York, NY; Regeneron Research Laboratories, Tarrytown, NY (ZL).
authors.forename: Sanjay
authors.initials: S
authors.lastname: Koul
authors.affiliation: Biomedical Research Foundation, Academy of Athens, Athens, Greece (DS, AP, CA, ZC, CT, AK, AE); Department of Pathology and Cell Biology (MS) and Division of Hematology/Oncology (SK), Columbia University Medical Center, New York, NY; Regeneron Research Laboratories, Tarrytown, NY (ZL).
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
authors.affiliation: Biomedical Research Foundation, Academy of Athens, Athens, Greece (DS, AP, CA, ZC, CT, AK, AE); Department of Pathology and Cell Biology (MS) and Division of Hematology/Oncology (SK), Columbia University Medical Center, New York, NY; Regeneron Research Laboratories, Tarrytown, NY (ZL).
authors.forename: Alexander
authors.initials: A
authors.lastname: Polyzos
authors.affiliation: Biomedical Research Foundation, Academy of Athens, Athens, Greece (DS, AP, CA, ZC, CT, AK, AE); Department of Pathology and Cell Biology (MS) and Division of Hematology/Oncology (SK), Columbia University Medical Center, New York, NY; Regeneron Research Laboratories, Tarrytown, NY (ZL).
authors.forename: Constantinos
authors.initials: C
authors.lastname: Anagnostopoulos
authors.affiliation: Biomedical Research Foundation, Academy of Athens, Athens, Greece (DS, AP, CA, ZC, CT, AK, AE); Department of Pathology and Cell Biology (MS) and Division of Hematology/Oncology (SK), Columbia University Medical Center, New York, NY; Regeneron Research Laboratories, Tarrytown, NY (ZL).
authors.forename: Zoe
authors.initials: Z
authors.lastname: Cournia
authors.affiliation: Biomedical Research Foundation, Academy of Athens, Athens, Greece (DS, AP, CA, ZC, CT, AK, AE); Department of Pathology and Cell Biology (MS) and Division of Hematology/Oncology (SK), Columbia University Medical Center, New York, NY; Regeneron Research Laboratories, Tarrytown, NY (ZL).
authors.forename: Constantin
authors.initials: C
authors.lastname: Tamvakopoulos
authors.affiliation: Biomedical Research Foundation, Academy of Athens, Athens, Greece (DS, AP, CA, ZC, CT, AK, AE); Department of Pathology and Cell Biology (MS) and Division of Hematology/Oncology (SK), Columbia University Medical Center, New York, NY; Regeneron Research Laboratories, Tarrytown, NY (ZL).
authors.forename: Apostolos
authors.initials: A
authors.lastname: Klinakis
authors.affiliation: Biomedical Research Foundation, Academy of Athens, Athens, Greece (DS, AP, CA, ZC, CT, AK, AE); Department of Pathology and Cell Biology (MS) and Division of Hematology/Oncology (SK), Columbia University Medical Center, New York, NY; Regeneron Research Laboratories, Tarrytown, NY (ZL). arg@bioacademy.gr.
authors.forename: Argiris
authors.initials: A
authors.lastname: Efstratiadis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D055879:Gene Knock-In Techniques; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D049268:Positron-Emission Tomography; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D013844:Thiazoles / Q000494:pharmacology*; D014057:Tomography, X-Ray Computed; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: C524814:5-(4-ethylbenzylidene)-2-thioxothiazolidin-4-one; D000970:Antineoplastic Agents; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D013844:Thiazoles; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)