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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：
10219703
负责人：
Bulent Ozpolat
金额：
$ 41.34万
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/10219703
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 Lipids 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 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.

项目总结