Optimizing Therapeutic STING Agonism in Triple Negative Breast Cancer

优化三阴性乳腺癌的 STING 激动治疗

• 批准号: 10370423
• 负责人: Thanh Uyen Barbie
• 金额: $ 40.72万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10370423
• 关键词: 4T1; AGFG1 gene; Agonist; Breast Cancer Model; Breast Cancer Prevention; Breast Cancer cell line; Breast biopsy; Cells; Clinical; Clinical Trials; Data; Development; Dinucleoside Phosphates; Drug Delivery Systems; Drug Kinetics; Drug usage; Exonuclease; Extravasation; Fostering; Genetic; Goals; Growth; Health; Human; Hyperactivity; Hypersensitivity; IKKepsilon; Immune signaling; Immunotherapy; Impairment; Injections; Innate Immune Response; Knock-out; Knowledge; Laboratory Study; Lead; Lysosomes; Malignant Neoplasms; Methods; Mission; Modeling; Mus; Nature; Outcome; PTEN gene; Pathway interactions; Patients; Periodicity; Pharmaceutical Preparations; Pharmacology; Phase I Clinical Trials; Phosphotransferases; Polyethylene Glycols; Polymers; Precision therapeutics; Prognosis; Public Health; RAS Superfamily Proteins; Reporting; Research; Research Personnel; Rodent; Role; STING agonists; STING1 gene; Secondary to; Signal Transduction; Solid; Stimulator of Interferon Genes; System; T-Lymphocyte; TBK1 gene; Testing; Therapeutic; Three Prime Repair Exonuclease 1; Tissues; Toxic effect; Translations; Treatment Efficacy; Tumor Immunity; United States National Institutes of Health; Up-Regulation; analog; anti-PD1 therapy; base; biomarker-driven; breast malignancies; cancer cell; cancer immunotherapy; clinical application; clinical translation; clinically actionable; cytokine; ds-DNA; effective therapy; evidence base; exodeoxyribonuclease; first-in-human; improved; in vivo; inhibitor; innovation; insight; interest; mouse model; neoplastic cell; novel strategies; novel therapeutic intervention; novel therapeutics; prevent; recruit; response; trafficking; treatment response; trend; triple-negative invasive breast carcinoma; tumor; tumor microenvironment

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.

项目总结