Could STING activation be the target of future cancer immunotherapies?
Researchers demonstrate that their novel small molecule, which activates the STING protein, supresses tumour growth and metastasis in a murine model of aggressive melanoma.
Scientists have developed a molecule that can remain stable in the circulation and activate STING (STimulator of INterferon Genes), a natural antitumour activity promoting protein. The developers say their novel small molecule could be highly influential in the field of oncology.
STING directs the immune system to act against viral and cancerous invaders and, because of its role in promoting antitumour immunity, has garnered enthusiastic interest from drug developers.
However, its natural activators in the body (eg, cyclic guanosine monophosphate–adenosine monophosphate [cGMP]) are unstable DNA-related molecules that do not last long in the bloodstream. This has hindered the development of treatments based on them and has prompted a search for a more stable STING-activating small molecule – one that can circulate in the blood and work against tumours systemically (ie, wherever they may exist in the body).
The scientists from The Scripps Research Institute (TSRI), who published their findings in Science, screened a set of suitable small molecules with diverse structures and identified several that activate STING. After modifying one of these molecules to optimise its properties, they found that delivering it systemically into mice with an injection greatly reduced the growth of an aggressive form of melanoma.
The discovery raises the possibility of a circulating drug that could activate STING and suppress a wide range of cancers:
“A systemic STING-activating molecule could have considerable utility, and not only as a therapeutic for cancer and infectious disease, but also as a probe for studying STING-dependent antitumor immunity and a host of other STING-related biological processes,” explained the study’s co-senior author, Dr Luke Lairson, an associate professor in the Department of Chemistry at TSRI.
Using X-ray crystallography to image the interaction of their optimised STING-activator, which they named SR-717, and cGMP with STING at atomic scale, they showed that both bind to the same site on STING and induce the same shape-change in the protein. They concluded from this that SR-717 appears to activate the STING protein in the same way as the natural activator.
In an animal model of aggressive melanoma, SR-717 dramatically suppressed tumour growth, prevented metastasis, induced the presentation of tumour molecules to the immune system and robustly boosted levels of CD8+ T cells and NK cells around tumours – both immune cell types are known to be among the immune system’s best antitumor defences. The researchers also reported that, at this effective dose, there was no evidence of significant adverse side effects on the animals.
Lairson and colleagues concluded that they are continuing to study SR-717, with the hope of developing it into a new anticancer treatment that could be used alone or in combination with other treatments.