Abstract LB-260: A small molecule Myc inhibitor has therapeutic effects on mouse pancreatic and other cancers

Abstract Mouse models faithfully simulating human cancer are valuable for genetic identification of potential drug-targets but, among them, the most advantageous for practical use in subsequent preclinical testing of candidate therapeutic regimes are those exhibiting rapid tumor development. Considering that pancreatic ductal adenocarcinoma (PDA) is the deadliest of the major malignancies and an unresolved clinical problem, and that a KRAS mutation (predominantly in codon 12, such as KRASG12D; KRAS*) occurs with high frequency (∼90%) in PDA cases, we sought to develop a mouse PDA model that would exhibit high tumor incidence and short latency by ectopic overexpression of Kras*. This transgenic modification caused by two weeks postpartum the appearance of pancreatic intraepithelial neoplasia (PanIN), which evolved into invasive PDA within a week later, and resulted in a moribund condition at one month of age. Interestingly, however, this aggressive form of pancreatic tumorigenesis was effectively prevented by genetic ablation of Myc specifically in the pancreas On the basis of this observation, causally demonstrating that Kras* oncogenicity fully depends on unperturbed Myc activity, we tested with positive results the effective treatment of our mouse PDA model by using orally-administered Mycro3, a small-molecule inhibitor of Myc-Max dimerization. PET/CT image analysis demonstrated marked shrinkage of PDA, while immunohistochemical analyses showed an increase in cancer cell apoptosis and reduction in cell proliferation. Tumor growth was also drastically attenuated in Mycro3-treated NOD/SCID mice carrying orthotopic or heterotopic xenografts of human pancreatic cancer cells. In addition, Mycro3 was efficacious in treating xenografts generated either heterotopically or orthotopically (by tail-injection) using a human lung carcinoma cell line (KRASG12D) and also in treating KRAS-driven mouse mammary tumors. These results provide strong justification for eventual clinical evaluation of anti-Myc drugs as potential chemotherapeutic agents for the treatment of PDA and other Myc-dependent cancers. Citation Format: Dimitris Stellas, Matthias Szabolcs, Sanjay Koul, Zhe Li, Alexander Polyzos, Constantinos Anagnostopoulos, Zoe Cournia, Constantin Tamvakopoulos, Apostolos Klinakis, Argiris Efstratiadis. A small molecule Myc inhibitor has therapeutic effects on mouse pancreatic and other cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-260. doi:10.1158/1538-7445.AM2015-LB-260