Abstract A012: Repurposing of the macrolide antibiotic clarithromycin for the prevention of lung cancer

Lung adenocarcinoma (LUAD), particularly K-ras mutant LUAD, is a leading cause of cancer mortality. Therefore, strategies to prevent K-ras-mutant LUAD in its earliest stages in high-risk individuals (e.g., smokers) are urgently needed to reduce the public burden of this fatal disease. We and others have shown that K-ras driven tumorigenesis in lung is intimately linked to chronic inflammation and ultimately, tumor cells immune-escape. The antibiotic clarithromycin (CAM) was identified as one of the most promising candidates for repurposing with demonstrated immunomodulatory and anticancer properties. CAM is widely used and belongs to the macrolide class of antibiotics which are among the safest broad spectrum antimicrobials available. Abundant preclinical and clinical evidence exists demonstrating the in vitro and in vivo anticancer effects of CAM. It has been shown that macrolide antibiotics exert suppression of inflammation without overt immunosuppressive effects mostly through the inhibition of proinflammatory cytokines in vitro and in vivo. In these studies, we tested the lung cancer prevention efficacy of CAM using a Kras mutant lung cancer model. In the CCSPCre; LSL-Kras- G12 D (CC-LR) model, activation of the KrasG12 D mutation takes place in club cells by means of removal of the lox-stop-lox genomic sequence via expression of Cre recombinase under the control of the CCSP promoter. This model is excellent for reproducing the various premalignant to malignant progression steps in the lung. CC-LR mice of both genders were randomly enrolled to four experimental arms comparing three CAM doses: 10mg/kg/day, 50mg/kg/day, and 100mg/kg/day, to vehicle control (H2O). Treatment was administered by oral gavage, 5 times per week for 10 wks., starting at 4 wks. of age. At 14 wks. of age mice were euthanized, lung surface tumors were counted, bronchial lavage fluid, as well as lung samples, were obtained for histological, immunohistochemical (IHC) and qRT-PCR analyses. Clarithromycin treatment led to significant lung cancer prevention efficacy, as determined by lung surface tumor counts. A clear dose response with CAM was observed with a mean lung surface tumor count of 30.2 tumors per mouse for vehicle (n=12 mice), 23.5 for CAM 10mg/kg (n=8), 18.8 for CAM 50mg/kg (n=8) and 13.5 tumors per mouse for the CAM 100mg/kg treatment group (n=12, p=0.0014). A significant decrease in the incidence and multiplicity of premalignant and malignant lesions was also observed in