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: 10596527
• 负责人: Thanh Uyen Barbie
• 金额: $ 39.9万
• 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/10596527
• 关键词: 4T1; Agonist; Breast Cancer Model; Breast Cancer Prevention; Breast Cancer cell line; Breast biopsy; Cells; Clinical; Clinical Trials; Creativeness; Cytoplasm; Data; Development; Dinucleoside Phosphates; Drug Delivery Systems; Drug Kinetics; Drug usage; Exonuclease; Extravasation; Fostering; Gene Activation; Gene Expression; Genetic; Goals; Growth; Health; Human; Hyperactivity; IKKepsilon; Immune signaling; Immunotherapy; Impairment; Injections; Innate Immune Response; Knock-out; Knowledge; Laboratory Study; Lysosomes; Malignant Neoplasms; Methods; Mission; Modeling; Mus; Nature; Outcome; PTEN gene; Pathway interactions; Patients; Periodicity; Pharmaceutical Preparations; Phase I Clinical Trials; Phosphotransferases; Polyethylene Glycols; Polymers; Precision therapeutics; Prognosis; Public Health; RAS Superfamily Proteins; Reporting; Research; Research Personnel; Rodent; Role; 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; 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; gene function; improved; in vivo; inhibitor; innovation; insight; interest; mouse model; neoplastic cell; novel strategies; novel therapeutic intervention; novel therapeutics; pharmacologic; prevent; recruit; response; therapeutic gene; 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.

项目摘要 尽管STING激动剂在癌症中的治疗前景，但首先在人类研究中受到以下因素的阻碍： 缺乏精确治疗和药物输送问题。我的实验室研究三阴性乳腺癌 TNBC是一种高度侵袭性的乳腺恶性肿瘤，治疗选择有限，预后不良。最近， 我们揭示了在TNBC的主要亚群中过度活跃的先天免疫信号传导的机制基础。 具体地说，我们发现PTEN的缺失与激酶TBK 1/IKK 3到KIRRab 7合谋，这限制了 STING的溶酶体降解。这使得PTEN缺失型TNBC对STING激动剂特别敏感。我们 长期目标是利用这些知识来开发有效的基于STING激动剂的TNBC免疫疗法。 总体目标是建立在我们的初步研究结果基础上，更普遍地增强STING激动剂的疗效。 通过防止STING降解和改善STING激动剂递送来抑制TNBC中的STING。我们的核心假设是 肿瘤细胞中延长的STING激动将更有效地消除TNBC生长并增强抗肿瘤活性。 免疫力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。核心假设是 通过追求三个特定目标进行测试：1）通过抑制Rab 7增加STING细胞保留; 2）靶向适应性 TREX 1上调以增强cGAS-STING上游活化;和3）体内检查和比较 STING激动剂在通过肿瘤内注射递送时的药代动力学和抗肿瘤功效与 浸渍在聚乙二醇化乳腺活检标记物中。考虑到我们的发现， 为了通过维持Rab 7处于失活状态来降解STING，我们将在第一个目标中研究Rab 7是否 抑制剂CID 1067700和Rab 7敲除可以将STING激动作用扩大到PTEN WT TNBC。根据第二个 目的是，我们将测试通过TREX 1抑制增加胞质dsDNA水平是否会进一步过度激活 cGAS-STING功能。在第三个目标中，使用4 T1 TNBC小鼠模型，我们计划将STING激动剂嵌入到 将含有聚乙二醇聚合物的预先存在的乳腺活检标记物作为临床上立即 与肿瘤内注射相比，在肿瘤微环境中维持STING激动作用的可行方式。的 本申请中提出的研究是创新的，在申请人看来，因为它代表了一个实质性的 通过解决STING降解和激动剂持续时间的基本问题， 通过多方面的方法进行曝光。拟议的研究是重要的，因为它预计将有一个 通过提供强有力的循证方法来在临床中保留STING激动作用， 试验设置，以便对治疗结果进行解释，并且不归因于不良结局 药物渗漏或STING的细胞内在降解。最终，这些知识有可能 为TNBC患者发现一种新的治疗策略，其中存在未满足的需求。