Unleashing the immune system's 'STING' against cancer
Date:
August 20, 2020
Source:
Scripps Research Institute
Summary:
Scientists have discovered a molecule that can activate a natural
immune- boosting protein called STING. The findings mark a key
advance in the field of oncology, as the STING protein is known
for its strong antitumor properties.
FULL STORY ========================================================================== Scientists at Scripps Research have discovered a molecule that can
activate a natural immune-boosting protein called STING. The findings
mark a key advance in the field of oncology, as the STING protein is
known for its strong antitumor properties.
========================================================================== STING (short for STimulator of INterferon Genes) 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 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 hardier STING-activating small molecule -- one that can circulate
in the blood and work against tumors "systemically," wherever they may
exist in the body.
The Scripps Research scientists, who report their finding in Science
on August 20, screened a set of suitable small molecules with diverse structures and identified several that activate STING. 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 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," says co-senior author Luke
Lairson, PhD, an associate professor in the Department of Chemistry at
Scripps Research.
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.
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.
Lairson and colleagues 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.
The work was a collaboration of Lairson's lab, the lab of John Teijaro,
PhD, associate professor in the Department of Immunology and Microbiology
at Scripps Research, and the lab of Mike Petrassi, PhD, vice president
of Medicinal Chemistry at Scripps Research's drug development arm,
Calibr. The project was led by first author Emily Chin, PhD, a staff
scientist in the Lairson lab, with Vincent Vartabedian and Ying Jia
conducting the in vivo characterization of SR- 717, and Chenguang Yu,
PhD, leading the medicinal chemistry efforts.
"Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic" was written by Emily Chin, Chenguang Yu, Vincent Vartabedian,
Ying Jia, Manoj Kumar, Ana Maria Gamo Albero, William Vernier, Sabrina
Ali, Mildred Kissai, Daniel Lazar, Nhan Nguyen, Laura Pereira, Brent
Benish, Ashley Woods, Sean Joseph, Alan Chu, Kristen Johnson, Philipp
Sander, Francisco Martinez- Pena, Eric Hampton, Travis Young, Dennis
Wolan, Arnab Chatterjee, Peter Schultz, Michael Petrassi, John Teijaro,
and Luke Lairson, all of Scripps Research during the study.
========================================================================== Story Source: Materials provided by Scripps_Research_Institute. Note:
Content may be edited for style and length.
========================================================================== Journal Reference:
1. Emily N. Chin, Chenguang Yu, Vincent F. Vartabedian, Ying Jia, Manoj
Kumar, Ana M. Gamo, William Vernier, Sabrina H. Ali, Mildred Kissai,
Daniel C. Lazar, Nhan Nguyen, Laura E. Pereira, Brent Benish,
Ashley K.
Woods, Sean B. Joseph, Alan Chu, Kristen A. Johnson, Philipp
N. Sander, Francisco Marti'nez-Pen~a, Eric N. Hampton, Travis
S. Young, Dennis W.
Wolan, Arnab K. Chatterjee, Peter G. Schultz, H. Michael Petrassi,
John R. Teijaro, Luke L. Lairson. Antitumor activity of a systemic
STING- activating non-nucleotide cGAMP mimetic. Science, 2020 DOI:
10.1126/ science.abb4255 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2020/08/200820164113.htm
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