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

• 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
• 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

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.

项目摘要 三阴性乳腺癌（TNBC）的患者死亡率最高。一些 已经确定了用于乳腺癌治疗的分子靶标，但目前尚无批准， 广泛适用于TNBC的目标治疗。通过10年的研究，我们发现伸长因素 2-激酶（EF2K）表达是TNBC肿瘤发生和进展的关键驱动力。我们还发现 MicroRNA-22（miR-22）表达在TNBC患者中被广泛抑制，并且与EF2K成反比 表达。进一步的分析表明，miR-22通过特异性结合EF2K抑制肿瘤。 抑制EF2K表达并减少多种TNBC模型中的肿瘤生长。考虑临床 EF2K在TNBC中的意义和潜在的治疗值，因此我们开发了一个靶向AXL受体的 AXL适体涂层的SLNP-MIR-22纳米颗粒系统，该系统可以特异性地向TNBC肿瘤传递miR-22 体内（但不会导致正常组织中的miR-22积累）。 在这项初步工作的基础上，我们假设EF2K是TNBC的有效治疗靶标，并且 使用我们的AXL-Appamer-SLNP-MIR-22纳米疗法来靶向EF2K可以提供重要的治疗 TNBC治疗的功效。但是，可以理解的是，这种治疗系统很复杂，而且 难以进一步理解显着影响的基本生物学和物理过程 治疗结果，并确定最佳剂量和剂量时间表以最大化治疗 功效。因此，在这个项目中，我们建议通过整合生物学实验来克服这一挑战 使用基于与基于基础的生物学和物理机制的数学建模有关 EF2K靶向的miR-22中的癌症入侵，药物渗透和吸毒细胞相互作用 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（AIM 1）和2）数学建模（AIM 2）。在AIM 1中，我们将专注于表征和确定EF2K靶向的体内治疗功效 原位小鼠模型中的miR-22介导的疗法。在AIM 2中，我们将专注于开发，测试和 使用逻辑集成 统计和多尺度机械建模方法。 AIM 1的实验数据将提供为AIM 2用于开发和验证数学模型，AIM 1中的实验将由发现指导 通过AIM 2中的计算调查获得。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 剂量和给药时间表，关于肿瘤对EF2K靶向的miR-22介导的疗法的反应（有或没有 化学疗法），并确定优化治疗的最佳药物剂量和剂量时间表 功效。该项目的长期目标是证明这种基于miR-22的纳米疗法是安全的，并且 有效，单独并与标准化学治疗剂一起作为共辅助治疗，并结合使用 为TNBC患者的潜在临床临床翻译完成临床前开发。