Abstract 2344: The cGAS-STING pathway is a therapeutic target in a preclinical model of hepatocellular carcinoma

Abstract

Abstract Activation of the STING pathway is currently being explored in cancer immune therapy. The first STING agonist tested was DMXAA, but failed in clinical trial, since it does not bind human STING. The second generation of STING agonists are cyclic di-nucleotides (CDNs), either the naturally produced 2’3’ cyclic GMP-AMP or derivatives, and many of these has proven to have high affinity for all common human variations of STING. In our work, we have focused on 3’3’-cyclic 3’3’-cAIMP (Invivogen) for analysis of anticancer activity in mice. Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and the incidence of HCC is increasing. We have used a mouse model of mutagen-induced HCC to explore the therapeutic usefulness of targeting the DNA-activated STING pathway in HCC. STING-deficient mice exhibited unaltered initial development of HCC, but had higher number of large tumors at late stages of disease. In the liver of STING-deficient HCC mice, we observed reduced levels of phospho-STAT1, autophagy, and cleaved caspase 3. These responses were activated in the liver by treatment with a cyclic dinucleotide (CDN) STING agonist. Importantly, CDN treatment of mice after HCC development efficiently reduced tumor size. Initiation of CDN treatment at an even later stage of disease to allow HCC detection by MR scanning, revealed that the majority of tumors regressed in response to CDN, but new tumors were detected, which were unresponsive to CDN treatment. Conclusion: modulation of the STING pathway impacts on development of HCC, and holds promise for use in treatment of this disease, most likely in combination with other immunomodulatory treatments such as PD1 inhibitors or with standard of care. Citation Format: Martin K. Thomsen. The cGAS-STING pathway is a therapeutic target in a preclinical model of hepatocellular carcinoma [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 2344.