Simultaneous targeting of tumor cells and tumor associated macrophages by RNA nanovector

RNA纳米载体同时靶向肿瘤细胞和肿瘤相关巨噬细胞

• 批准号: 10201989
• 负责人: Tae Jin Lee
• 金额: $ 15.6万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201989
• 关键词: Ache; Anaplastic astrocytoma; Astrocytes; Bacteriophages; Biodistribution; Blood - brain barrier anatomy; Brain Neoplasms; CD44 gene; Cell Proliferation; Cells; Clinical; Clinical Trials; DNA Packaging; Development; Down-Regulation; Drug Kinetics; Engineering; Epidermal Growth Factor Receptor; Excision; Folic Acid; Gene Expression; Glioblastoma; Glioma; Human; Immune; Immune Evasion; Immunity; Immunocompetent; Immunodeficient Mouse; Immunotherapy; Infiltration; Ligands; Malignant Neoplasms; Mediating; Methods; MicroRNAs; Modeling; Motor; Mus; Natural Immunity; Neurons; Normal Cell; Oncogenic; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pharmacologic Substance; Phenotype; Preclinical Testing; Predisposition; RNA; Radiation; Resistance; Role; Signal Pathway; Site; Small Interfering RNA; Small RNA; Survival Rate; System; T-Cell Activation; Testing; Therapeutic; Therapeutic Agents; Tissues; Translating; Tumor Escape; Tumor-Derived; Tumor-associated macrophages; Xenograft procedure; adaptive immune response; adaptive immunity; anti-tumor immune response; antitumor agent; aptamer; base; blood-brain tumor barrier; cancer cell; cancer type; cell killing; chemotherapy; conventional therapy; cytokine; folate-binding protein; improved; innovation; macrophage; mouse model; nanovector; neoplastic cell; novel; novel therapeutics; overexpression; pre-clinical; preclinical study; programmed cell death ligand 1; receptor; response; restoration; targeted delivery; targeted treatment; temozolomide; therapeutic miRNA; therapeutic target; therapy outcome; tool; tumor; tumor microenvironment; tumor-immune system interactions; tumor-specific gene delivery

PROJECT SUMMARY/ABSTRACT Compared to other types of cancer that have benefited from considerable advances in therapy, therapeutic outcomes in glioblastoma (GBM) patients still remains dismal due to its resistance to conventional therapies. Such poor response is often related to aberrant dysregulation of gene expressions in tumor cell and tumor- supportive tumor microenvironment (TME) that is educated by the tumor cell through immune editing, indicating that the tumor is not primed for the treatment due to the unfavorable gene expressions. In order to prime the tumor cells and the immunosuppressive TME to improve the clinical outcomes in GBM patients from current treatment options or even new therapeutics, both tumor cells and tumor-associated macrophages (TAMs) need to be reprogrammed by reversing the aberrantly dysregulated gene expressions across various signaling pathways. Tumor suppressive microRNAs (miRNAs) have been proposed as the most suitable therapeutic target to perform the tumor reprogramming role. We recently found that a putative tumor suppressive miRNA, miR-138, has a potential to reprogram GBM tumor cells through down-regulation of major oncogenic pathways CD44 and EGFR, which governs cell proliferation and immune evasion through PD-L1 and cytokine expressions. However, little progress has been made in miRNA-based therapy mainly due to the lack of efficient and safe targeted delivery method into tumor cells across the blood brain tumor barrier (BBTB). In addition, dual targeting of both tumor cells and TAMs to delivery such therapeutically useful tumor suppressive miRNAs has never been attempted. Previously, we have shown that RNA nanovector (RNV) platform based on the Three-Way-Junction (3WJ) motif of packaging RNA (3WJ-pRNA) in the DNA packaging motor of bacteriophage phi29 with conjugation of folate (FA) (FA-RNV) has a potential to selectively target folate receptor (FR) positive GBM cells and deliver a small RNA with favorable bio-distribution and pharmacokinetic profiles in mice model. We hypothesize that targeted delivery of tumor suppressive miR-138 into GBM tumor cells and TAMs by our ligand-conjugated RNV will reprogram both GBM tumor and tumor- associated innate immunity to result better tumor regression through direct tumor cell killing and susceptibility to conventional immunotherapy. Here, we propose to optimze the RNV derived from the three-way junction (3WJ) motif to achieve this challenging task by testing different cell-specific ligand or RNA aptamers (Aim 1). In addition, we will test the preclinical impact of simultaneous targeted delivery of miR-138 into tumor cells and TAMs by cell-specific RNVs (Aim 2). To our knowledge, this is the first preclinical study attempting to simultaneously modulate tumor cells and innate immunity by delivering a tumor suppressive miRNA using the RNV delivery system for GBM treatment. Our study results can be rapidly translated into human clinical trials in a combination with current immunotherapies.

项目摘要/摘要 与其他类型的癌症相比，这些癌症受益于治疗的大量进展 胶质母细胞瘤（GBM）患者的预后由于对常规疗法的抗性，仍然仍然令人沮丧。 这种不良反应通常与肿瘤细胞和肿瘤中基因表达的异常失调有关 肿瘤细胞通过免疫编辑教育的支持性肿瘤微环境（TME）， 表明由于基因表达不良而导致肿瘤未进行治疗。为了 为肿瘤细胞和免疫抑制性TME加油，以改善来自GBM患者的临床结果 当前的治疗选择甚至是新的治疗剂，肿瘤细胞和与肿瘤相关的巨噬细胞都 （TAM）需要通过逆转各种基因表达的异常失调的基因表达来重新编程 信号通路。肿瘤抑制microRNA（miRNA）已被认为是最合适的 治疗目标以执行肿瘤重编程角色。我们最近发现一个假定的肿瘤 抑制性miRNA，miR-138，有可能通过下调主要的 致癌途径CD44和EGFR，它通过PD-L1控制细胞增殖和免疫逃避 和细胞因子表达。但是，基于miRNA的治疗几乎没有取得进展，主要是由于 缺乏在血液脑肿瘤屏障（BBTB）跨肿瘤细胞中的有效且安全的靶向递送方法。 此外，肿瘤细胞和TAM的双重靶向这种治疗有用的肿瘤 抑制性miRNA从未尝试过。以前，我们已经表明RNA纳米炉（RNV） 基于DNA包装中包装RNA（3WJ-prNA）的三向连接（3WJ）图案的平台 噬菌体Phi29的电动机与叶酸（FA）（FA-RNV）的偶联性有选择性靶向 叶酸受体（FR）阳性GBM细胞，并提供一个具有良好生物分布的小RNA， 小鼠模型中的药代动力学特征。我们假设有针对性的肿瘤抑制miR-138 通过我们的配体偶联的RNV进入GBM肿瘤细胞和TAM，将重新编程GBM肿瘤和肿瘤 相关的先天免疫力通过直接肿瘤细胞杀伤和易感性导致更好的肿瘤回归 进行常规免疫疗法。在这里，我们建议最佳从三向交界处得出的RNV （3WJ）主题通过测试不同细胞特异性配体或RNA适体（AIM 1）来实现这一具有挑战性的任务。 此外，我们还将测试同时将miR-138靶向递送到肿瘤细胞和 通过细胞特异性RNV的TAM（AIM 2）。据我们所知，这是第一个试图进行的临床前研究 同时通过使用抑制肿瘤的miRNA来调节肿瘤细胞和先天免疫 GBM治疗的RNV输送系统。我们的研究结果可以迅速转化为人类的临床试验 与当前免疫疗法的结合。

项目成果

Therapeutic Application of Brain-Specific Angiogenesis Inhibitor 1 for Cancer Therapy.

• DOI: 10.3390/cancers13143562
• 发表时间: 2021-07-16
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Nair M;Bolyard C;Lee TJ;Kaur B;Yoo JY
• 通讯作者: Yoo JY