Scientists at Scripps Research have discovered a molecule that can activate a natural immune-boosting protein called STING (short for STimulator of INterferon Genes). The findings mark a key advance in the field of oncology, as STING protein is known for its strong antitumor properties. STING marshals the immune system against viral and cancerous invaders and, because of its role in promoting antitumor immunity, has garnered enthusiastic interest from drug developers. However, STING’s natural activators in the body are unstable DNA-related molecules (cellular, bacterial, viral and the like) that do not last long in the bloodstream. That has hindered the development of treatments based on them, and has prompted a search for a stable one that can circulate in the blood and work against tumors “systemically”. The Scripps Research scientists, who report their finding in the journal Science, screened a set of suitable small molecules with diverse structures and identified several that activate STING.
The discovery raises the possibility of a circulating drug that could activate STING and suppress a wide range of cancers. According to Dr. Luke Lairson, PhD and associated professor at the Department of Chemistry, a systemic STING-activating molecule could have considerable utility, and not only for cancer and infectious disease, but also as a probe for studying STING-dependent antitumor immunity and other STING-related biological processes. Lairson and colleagues found that their optimized STING-activator, which they named SR-717, appears to activate the STING protein in the same way as its natural activators in the body. Using X-ray crystallography to image the interaction at atomic scale, they showed that both SR-717 and a known natural activator bind to the same site on STING and induce the same shape-change in the protein. After modifying one of these molecules to optimize its properties, they found that delivering it systemically into mice with an injection greatly reduced the growth of melanoma cells.
In an animal model of aggressive melanoma, SR-717 dramatically suppressed tumor growth, prevented metastasis, induced the presentation of tumor molecules to the immune system, and robustly boosted levels around tumors of CD8+ T cells and NK cells, both of which are known to be among the immune system’s heaviest antitumor weapons. At this effective dose, there was no evidence of significant adverse side effects on the animals. But this is not tha only molecule available. Another research team working at Merck Industries has discovered a non-nucleotide synthetic activator of STING In syngeneic mouse tumor models, subcutaneous and oral MSA-2 regimens were well tolerated and stimulated interferon-β secretion in tumors, induced tumor regression with durable antitumor immunity, and synergized with anti-PD-1 checkpoint immunotherapy. Moreover, cellular potency of MSA-2 increased upon extracellular acidification, which mimics the tumor microenvironment.
The search for STING agonists, both nucletotide-type and non, is not new however; it started in 2014 and its been about small synthetic molecules. Another, called BNBC was discovered last year by a team from the Baruch Institute in Pennsylvania. This molecule not only induced innate antiviral immunity against a broad spectrum of viruses but may also stimulated the activation of adaptive immune response, which is important for treatment of chronic viral infections and tumors. Overall, the finding of an almost perfect STING agonist would allow clinicians to better treat conditions which represent either a considerable challenge and burden for the public health.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Chin EN et al. Science 2020 Aug 21; 369(6506):993-999.
Pan BS et al. Science. 2020 Aug 21; 369(6506):eaba6098.
Wang-Bishop L et al. J Immunother Cancer 2020; 8(1).
Ager CR et al. Bioorg Med Chem Lett 2019; 29(20):126640.