Abstract 2349: Modulation of inflammation in the tumor microenvironment by ER and PPARγ in an NNK-induced lung carcinogenesis model

Lung cancer is the number one cause of cancer-related fatalities, and to date, there are no FDA-approved chemoprevention options for lung cancer prevention. NNK, the principal carcinogen in cigarette smoke can induce mutations in oncogenes and can also act as an inflammatory mediator of the tumor microenvironment (TME) by promoting macrophage infiltration into the lungs. Macrophages play a key role in regulation of the lung TME. Pioglitazone, a synthetic peroxisome proliferator-activated receptor gamma (PPARγ) agonist belonging to the thiazolidinediones (TZDs) drug class has been used in preclinical studies to mitigate lung tumorigenesis, progression, and metastasis. A retrospective analysis found that diabetics using TZDs experienced a 33% reduction in lung cancer incidence. Cross-talk between PPARγ and estrogen receptor (ER) signaling has been previously reported, and ER has already been implicated as a driver of lung cancer severity. Both ER and PPARγ are also known to be functional in macrophages. Agents that block ER signaling such as fulvestrant, a complete ER antagonist, have shown activity against lung cancer. We therefore tested the ability of pioglitazone and fulvestrant in combination to reduce lung tumor formation and to modulate the TME. Preliminary results from a co-culture simulation of the TME in vitro using human macrophages and lung adenocarcinoma cells show pioglitazone and fulvestrant together can significantly suppress inflammatory modulators such as IL-1β, IL-10, Amphiregulin (AREG), and VEGF compared to single treatments. Similar effects were observed in a mouse model system of the TME. This drug combination also reduced number of tumor cell colonies in a soft agar assay, suggesting a direct effects on tumor cells. In vivo use of combined pioglitazone and fulvestrant in an NNK female mouse model of former smokers showed a significant reduction in tumor size by 40% compared to placebo (p= 0.0010), 13% by pioglitazone alone and 5% by fulvestrant alone. Inflammatory cytokine array analysis of the bronchio-alveolar lavage fluid (BALF) revealed maximum down-modulation of pro-tumor inflammatory mediators with combination treatment compared to single treatments. Fulvestrant alone did not suppress tumor-promoting inflammatory pathways, suggesting possible activation of compensatory signaling pathways. Further analysis of the cell cultures and the BALF confirmed EGFR compensatory activation through release of AREG with fulvestrant single treatment, that is suppressed with the addition of pioglitazone. Thus, the strong combination effect of pioglitazone and fulvestrant on lung tumor growth and macrophage function, and the ability of the combination to suppress compensatory signaling pathways, supports the hypothesis of ER/PPARγ cross-talk in lung cancer and provides a rationale for further investigation of chemopreventive effects of this combination. Citation Format: Erika Louiselle, Oshin Miranda, Huiyu Li, MiKayla Boeder, Zhijie Li, Jill M. Siegfried, Mariya Farooqui. Modulation of inflammation in the tumor microenvironment by ER and PPARγ in an NNK-induced lung carcinogenesis model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2349.