Nanoparticle delivery of miRNA-based therapeutics to overcome clinical challenges in triple negative breast cancer

纳米颗粒递送基于 miRNA 的疗法可克服三阴性乳腺癌的临床挑战

基本信息

批准号：
10364691
负责人：
Bulent Ozpolat
金额：
$ 39.01万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-04 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10364691
关键词：
Accounting Acute Adjuvant Chemotherapy Adjuvant Therapy Antineoplastic Agents Binding Biological Biological Markers Biological Process Biology Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer Treatment Cell Communication Cell Line Cells Chronic Clinical Complex Coupling Data Databases Death Rate Diffusion Dose Doxorubicin Drug Transport Drug resistance Feedback Fostering Future Goals Health In Vitro Investigation Malignant Neoplasms Malignant neoplasm of pancreas Maximum Tolerated Dose Mediating Methodology MicroRNAs Mission Modeling Molecular Target Neoplasm Metastasis Normal tissue morphology Organ Patients Penetration Pharmaceutical Preparations Pharmacology Physics Pre-Clinical Model Process Prognosis Relapse Research Safety Schedule Small Interfering RNA System Testing The Cancer Genome Atlas Therapeutic Time Toxic effect Treatment Efficacy Treatment outcome Tumor stage Tumor-infiltrating immune cells United States National Institutes of Health Work appropriate dose aptamer axl receptor tyrosine kinase base calmodulin-dependent protein kinase III cancer subtypes cancer therapy chemotherapeutic agent chemotherapy clinical practice clinical translation clinically significant dosage experimental study guided inquiry improved in vivo innovation lipid nanoparticle malignant breast neoplasm mathematical model model development mouse model nanoparticle nanoparticle delivery nanotherapeutic nanotherapy novel therapeutics pharmacokinetics and pharmacodynamics physical process preclinical development predictive modeling receptor response targeted delivery targeted treatment therapeutic miRNA therapeutic target therapeutically effective triple-negative invasive breast carcinoma tumor tumor growth tumor microenvironment tumorigenesis

项目摘要

Project Summary Triple-negative breast cancer (TNBC) has the highest patient death rate of all breast cancer subtypes. Several molecular targets have been identified for breast cancer treatment, but currently, there is no approved, broadly applicable targeted therapy for TNBC. Through 10 years of research, we found that elongation factor 2-kinase (EF2K) expression is a critical driver of TNBC tumorigenesis and progression. We also found that microRNA-22 (miR-22) expression is broadly repressed in TNBC patients, and is inversely correlated with EF2K expression. Further analysis revealed that miR-22 suppresses tumors by specifically binding to EF2K, which inhibits EF2K expression and reduces tumor growth in multiple TNBC models. Considering the clinical significance and potential therapeutic value of EF2K in TNBC, we have thus developed an AXL receptor-targeted AXL aptamer-coated SLNP-miR-22 nanoparticle system that can specifically deliver miR-22 to TNBC tumors in vivo (but does not lead to miR-22 accumulation in normal tissues). On the basis of this preliminary work, we hypothesize that EF2K is an effective therapeutic target in TNBC, and that targeting EF2K using our AXL-aptamer-SLNP-miR-22 nanotherapeutics can provide significant therapeutic efficacy in TNBC treatment. However, understandably, this therapeutic system is complex, and it has been difficult to further understand the underlying biological and physical processes that significantly impact treatment outcome, and to identify the optimal doses and dosing schedules for maximizing treatment efficacy. Therefore, in this project, we propose to overcome this challenge by integrating biological experiments with mathematical modeling based on the underlying biological and physical mechanisms that are involved in cancer invasion, drug penetration, and drug-cancer cell interactions in the EF2K-targeted miR-22 nanotherapeutics for TNBC treatment. Our hypothesis will be tested by achieving the following two specific aims: 1) experimental testing of the EF2K-targeted miR-22 nanotherapy (Aim 1), and 2) mathematical modeling (Aim 2). In Aim 1, we will focus on characterizing and determining the in vivo therapeutic efficacy of EF2K-targeted miR-22 mediated therapies in orthotopic mouse models. In Aim 2, we will focus on developing, testing, and validating a mathematical model of EF2K-targeted, miR-22 based nanotherapy, using a logically integrated statistical and multiscale mechanistic modeling approach. Experimental data from Aim 1 will be supplied to Aim 2 for developing and validating the mathematical model, and experiments in Aim 1 will be guided by discoveries obtained from computational investigations in Aim 2. Through this iteration-based feedback approach, the mathematical model will be used to predict and determine the effects of various parameters, including siRNA dose and dosing schedules, on tumor response to EF2K-targeted miR-22 mediated therapies (with or without chemotherapy), and to determine the optimal drug doses and dosing schedules for optimizing therapeutic efficacy. The long-term goal of this project is to demonstrate that this miR-22-based nanotherapy is safe and effective, both alone and in combination with standard chemotherapeutic agents as a co-adjuvant therapy, and to complete preclinical development for potential future clinical translation for TNBC patients.

项目概要三阴性乳腺癌（TNBC）是所有乳腺癌亚型中患者死亡率最高的。一些乳腺癌治疗的分子靶点已确定，但目前尚无批准的、广泛适用的TNBC靶向治疗。经过10年的研究，我们发现伸长因子 2-激酶 (EF2K) 表达是 TNBC 肿瘤发生和进展的关键驱动因素。我们还发现 microRNA-22 (miR-22) 表达在 TNBC 患者中广泛受到抑制，并且与 EF2K 呈负相关表达。进一步分析表明，miR-22通过与EF2K特异性结合来抑制肿瘤，在多种 TNBC 模型中抑制 EF2K 表达并减少肿瘤生长。考虑到临床为了认识到 EF2K 在 TNBC 中的重要性和潜在治疗价值，我们开发了一种 AXL 受体靶向药物 AXL 适体包被的 SLNP-miR-22 纳米颗粒系统可将 miR-22 特异性递送至 TNBC 肿瘤体内（但不会导致 miR-22 在正常组织中积累）。基于这项初步工作，我们假设 EF2K 是 TNBC 的有效治疗靶点，并且使用我们的 AXL-aptamer-SLNP-miR-22 纳米疗法靶向 EF2K 可以提供显着的治疗效果 TNBC 治疗的疗效。然而，可以理解的是，这个治疗系统很复杂，而且已经难以进一步了解显着影响的潜在生物和物理过程治疗结果，并确定最佳剂量和给药方案以最大化治疗效果功效。因此，在这个项目中，我们建议通过整合生物实验来克服这一挑战基于所涉及的潜在生物和物理机制的数学模型 EF2K 靶向 miR-22 中的癌症侵袭、药物渗透和药物与癌细胞相互作用用于 TNBC 治疗的纳米疗法。我们的假设将通过实现以下两个具体目标来检验： 1) EF2K 靶向 miR-22 纳米疗法的实验测试（目标 1），以及 2) 数学模型（目标 2）。在目标 1 中，我们将重点描述和确定 EF2K 靶向药物的体内治疗功效原位小鼠模型中 miR-22 介导的治疗。在目标 2 中，我们将专注于开发、测试和使用逻辑集成验证 EF2K 靶向、基于 miR-22 的纳米疗法的数学模型统计和多尺度机械建模方法。 Aim 1 的实验数据将提供给 Aim 2 用于开发和验证数学模型，目标 1 中的实验将以发现为指导从目标 2 中的计算研究中获得。通过这种基于迭代的反馈方法，数学模型将用于预测和确定各种参数的影响，包括siRNA 剂量和给药方案，关于肿瘤对 EF2K 靶向 miR-22 介导的疗法（有或没有化疗），并确定最佳药物剂量和给药方案以优化治疗功效。该项目的长期目标是证明这种基于 miR-22 的纳米疗法是安全且有效的。单独使用或与标准化疗药物联合作为辅助辅助治疗均有效，并且完成临床前开发，以实现未来针对 TNBC 患者的潜在临床转化。