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.

项目概要 尽管 STING 激动剂在癌症方面具有治疗前景，但首先在人类研究中却受到了阻碍 缺乏精准治疗和药物输送问题。我的实验室研究三阴性乳腺癌 （TNBC），一种高度侵袭性的乳腺恶性肿瘤，治疗选择有限且预后不良。最近， 我们发现了 TNBC 主要亚群中过度活跃的先天免疫信号传导的机制基础。 具体来说，我们发现 PTEN 丢失与激酶 TBK1/IKKepsilon 共同失活 Rab7，这限制了 STING 的溶酶体降解。这使得 PTEN 无效 TNBC 对 STING 激动剂特别敏感。我们的 长期目标是利用这些知识开发有效的基于 STING 激动剂的 TNBC 免疫疗法。 总体目标是基于我们的初步发现并更广泛地提高 STING 激动剂的功效 通过防止 STING 降解和改善 STING 激动剂输送来在 TNBC 中发挥作用。我们的中心假设是 肿瘤细胞中长时间的 STING 激动将更有效地消除 TNBC 生长并增强抗肿瘤作用 免疫。该项目的基本原理是在肿瘤微环境中保留 STING 激动作用的能力 将有助于提高其在临床环境中的治疗效果。中心假设将是 通过追求三个特定目标进行测试：1）通过抑制 Rab7 增加 STING 细胞保留； 2）目标自适应 TREX1 上调以促进上游 cGAS-STING 激活； 3) 体内检查和比较 通过肿瘤内注射与 STING 激动剂相比，STING 激动剂的药代动力学和抗肿瘤功效 浸渍在聚乙二醇化乳腺活检标记中。鉴于我们的发现，PTEN 无效 TNBC 可以预防 通过维持 Rab7 处于非活性状态来降解 STING，我们将在第一个目标中研究 Rab7 是否 抑制剂 CID1067700 和 Rab7 敲除可以扩大 STING 对 PTEN WT TNBC 的激动作用。第二下 目的，我们将测试通过 TREX1 抑制增加胞质 dsDNA 水平是否会进一步过度激活 cGAS-STING 功能。第三个目标，使用4T1 TNBC小鼠模型，我们计划嵌入STING激动剂 纳入预先存在的含有聚乙二醇聚合物的乳腺活检标记物中，作为立即的临床 与瘤内注射相比，在肿瘤微环境中维持 STING 激动的可行方法。这 申请人认为，本申请中提出的研究具有创新性，因为它代表了实质性研究 通过解决 STING 降解和激动剂持续时间这一基本问题来摆脱现状 通过多方面的方式进行曝光。拟议的研究意义重大，因为预计它会产生 通过提供强有力的基于证据的方法来在临床中保留 STING 激动作用，产生了重要的积极影响 试验环境，使得由此产生的治疗结果是可解释的并且负面结果不会被归因 药物泄漏或 STING 的细胞内在降解。最终，这些知识有可能 为尚未满足需求的 TNBC 患者揭示一种新的治疗策略。