Preclinical evaluation of 1,2-Diamino-4,5-Dibromobenzene in Genetically Engineered Mouse models of Pancreatic Cancer

Background: Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to standard chemoand radiotherapy. Recently, a new class of non-platinum-based halogenated molecules (called FMD compounds) was discovered that selectively kills cancer cells. Here, we investigate the potential of 1,2-Diamino-4,5-dibromobenzene (2Br-DAB) in combinationwith standard chemotherapy and radiotherapy in murine and human PDAC. Methods: Cell viability and colony formation was performed in human (Panc1, BxPC3, PaTu8988t,MiaPaCa) and threemurine LSL-Kras^G12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) pancreatic cancer cell lines. In vivo, preclinical experiments were conducted in LSL-KrasG12D/+;p48-Cre (KC) and KPC mice using 2Br-DAB (7 mg/kg, i.p.), +/- radiation (10 1.8 Gy), gemcitabine (100 mg/kg, i.p.), or a combination. Tumor growth and therapeutic response were assessed by high-resolution ultrasound and immunohistochemistry. Results: 2Br-DAB significantly reduced cell viability in human andmurine pancreatic cancer cell lines in a dose-dependentmanner. In particular, colony formation in human Panc1 cells was significantly decreased upon 25 μM 2Br-DAB + radiation treatment compared with vehicle control (p = 0.03). In vivo, 2Br-DAB reduced tumor frequency in KCmice. In the KPCmodel, 2Br-DAB or gemcitabinemonotherapy had comparable therapeutic effects. Furthermore, the combination of gemcitabine and 2Br-DAB or 2Br-DAB and 18 Gy irradiation showed additional antineoplastic effects. Conclusions: 2Br-DAB is effective in killing pancreatic cancer cells in vitro. 2Br-DABwas not toxic in vivo, and additional antineoplastic effects were observed in combination with irradiation. © 2019 by the authors.