Optimizing Therapeutic STING Agonism in Triple Negative Breast Cancer

PROJECT SUMMARY
Despite the therapeutic promise of STING agonists in cancer, first in human studies have been hampered by
lack of precision therapy and issues with drug delivery. My laboratory studies triple negative breast cancer
(TNBC), a highly aggressive breast malignancy with limited therapeutic options and a poor prognosis. Recently,
we uncovered the mechanistic basis for hyperactive innate immune signaling in a major subset of TNBCs.
Specifically, we found that PTEN loss conspires with the kinases TBK1/IKKepsilon to inactivate Rab7, which limits
lysosomal degradation of STING. This renders PTEN null TNBCs particularly sensitive to STING agonists. Our
long-term goal is to utilize this knowledge to develop effective STING agonist-based immunotherapy for TNBC.
The overall objectives are to build upon our initial findings and enhance STING agonist efficacy more generally
in TNBCs by preventing STING degradation and improving STING agonist delivery. Our central hypothesis is
that prolonged STING agonism in tumor cells will more effectively abrogate TNBC growth and boost anti-tumor
immunity. The rationale for this project is that the ability to retain STING agonism in the tumor microenvironment
will be instrumental to enhancing its therapeutic efficacy in the clinical setting. The central hypothesis will be
tested by pursuing three specific aims: 1) Increase STING cellular retention by inhibiting Rab7; 2) Target adaptive
TREX1 upregulation to boost cGAS-STING activation upstream; and 3) Examine and compare in vivo
pharmacokinetics and anti-tumor efficacy of STING agonist when delivered via intra-tumoral injection versus
impregnation in a PEGylated breast biopsy marker. Given our findings that PTEN null TNBCs prevent
degradation of STING by maintaining Rab7 in an inactive state, we will study in the first aim whether the Rab7
inhibitor CID1067700 and Rab7 knockout can broaden STING agonism to PTEN WT TNBCs. Under the second
aim, we will test whether increasing levels of cytosolic dsDNA through TREX1 inhibition will further hyperactivate
cGAS-STING function. In the third aim, using the 4T1 TNBC mouse model, we plan to embed STING agonists
into pre-existing breast biopsy markers containing polyethylene glycol polymers as an immediate clinically
actionable way to maintain STING agonism in the tumor microenvironment versus intratumoral injection. The
research proposed in this application is innovative, in the applicant's opinion, because it represents a substantive
departure from the status quo by tackling this essential problem of STING degradation and duration of agonist
exposure via a multifaceted approach. The proposed research is significant because it is expected to have an
important positive impact by providing a strong evidence-based method to retain STING agonism in the clinical
trial setting, such that resultant therapeutic findings are interpretable and negative outcomes are not attributed
to drug leakage or to cell intrinsic degradation of STING. Ultimately, such knowledge has the potential of
uncovering a new therapeutic strategy for patients with TNBC where there is an unmet need.

Grant Number: 5R01CA258688-05
NIH Institute/Center: NIH
Principal Investigator: Thanh Barbie