Abstract 3220: Small molecules related to adrenomedullin reduce tumor burden in a mouse model of colitis-associated colon cancer

Abstract

Abstract Adrenomedullin (AM) expression is elevated in colon cancer patients and a correlation between higher AM levels and lower disease-free survival has been described in Japan. Nevertheless, the influence of AM in colon cancer is somewhat controversial: on the one hand, antibodies against either the peptide or the receptor reduce the growth of xenografted tumors, whereas application of the peptide clearly reduces inflammation and clinical severity in human and mouse models of colitis, which is an important risk factor for colon cancer. To investigate the contribution of AM and its gene-related peptide, proadrenomedullin N-terminal 20 peptide (PAMP), to the progression and potential treatment of colon cancer we have studied the effects of several small molecules (SM) related to AM and PAMP on a mouse model of colon cancer. Colon tumors were induced by intraperitoneal injection of a carcinogen: 10 mg/Kg azoxymethane, followed by 3 cycles of a colitis-inducing chemical: 2.5% dextran sulfate sodium (DSS) in the drinking water for a week followed by 2 weeks of regular water. Four SM were tested: 16311 (a negative modulator of AM), 145425 (a positive modulator of AM), 87877 (a negative modulator of PAMP), and 106221 (a positive modulator of PAMP). For each SM, 4 experimental groups of male C57BL6 mice were used: i) Control group (injected with vehicle and drank regular water); ii) Control+SM (vehicle, regular water, and injected with the SM 3 times a week at a concentration of 20 nm/Kg); iii) Cancer group (injected with AOM and drank DSS); and iv) Cancer+SM (treated with AOM, DSS, and the SM). At the end of the experimental procedures, animals were sacrificed and the colon was extracted and analyzed. None of the mice belonging to groups i and ii developed any tumor or had any pathological finding, indicating that the SMs do not present overt toxicity. All mice in groups iii and iv developed colon neoplasias ranging from carcinomas in situ to adenocarcinomas. No significant differences were found among mice treated with PAMP modulators indicating that PAMP may not play a major role in colon cancer or that the PAMP-related SMs were not very effective. On the other hand, mice that received SM 16311 had a higher severity index (p<0.001) and weight loss (p<0.05) than their control counterparts, whereas mice injected with SM 145425 had a lower number of tumors than their controls (p<0.001). These results suggest that AM may have a protective role during the progression phase of colon cancer, and that treatment with AM or with positive modulator SMs may represent a novel treatment for colon cancer. This study was funded by Instituto de Salud Carlos III (PI13/02166), FEDER, and Junta Provincial de La Rioja de la Asociación Española Contra el Cáncer (AECC). Citation Format: Laura Ochoa-Callejero, Josune García-Sanmartín, Sonia Martínez-Herrero, Susana Rubio-Mediavilla, Alfredo Martínez. Small molecules related to adrenomedullin reduce tumor burden in a mouse model of colitis-associated colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3220. doi:10.1158/1538-7445.AM2017-3220