Towards Translation of MU-CN29: New Therapeutic Nanoparticle for Drug-Resistant NSCLC

MU-CN29 的转化：治疗耐药 NSCLC 的新型治疗纳米颗粒

基本信息

批准号：
10649533
负责人：
Raghuraman Kannan
金额：
$ 57.84万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-17 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649533
关键词：
Animal Cancer Model Animal Model Antibodies Automobile Driving Binding Biodistribution Biological Assay Bypass Cancer Etiology Cancer Model Cancer Patient Canis familiaris Cell Death Cells Chemoresistance Clinical Clinical Trials Combined Modality Therapy Data Disease remission Dose Down-Regulation Drug Kinetics Drug Targeting Drug resistance Epidermal Growth Factor Receptor Exhibits Future Gelatin Goals Guidelines Hepatic Human Immune Immune checkpoint inhibitor Immune response Immunocompetent Immunotherapy In Vitro Kidney Lead Libraries Malignant neoplasm of lung Metastatic Neoplasm to the Lung Mind Molecular Mus Mutate Mutation NF-kappa B Nanoconjugate Non-Small-Cell Lung Carcinoma Oncogenes Outcome Pathway interactions Patients Pharmaceutical Preparations Phenotype Production Proteins Protocols documentation Publishing Quality Control RNA Degradation Radiology Specialty Resistance Safety Signal Pathway Signal Transduction Small Interfering RNA Survival Rate System Therapeutic Therapeutic Agents Toxic effect Toxicology Translations Treatment Efficacy Tyrosine Kinase Inhibitor Woman Xenograft procedure acquired drug resistance analytical method axl receptor tyrosine kinase cancer therapy canine model checkpoint therapy clinical efficacy clinical translation clinically relevant combat efficacy evaluation immune resistance immunoregulation improved in vivo in vivo Model inhibitor inhibitor therapy knock-down large scale production lung cancer cell manufacture men mortality mouse model mutant nanoparticle nanoparticle drug novel novel strategies novel therapeutics overexpression protein expression response safety assessment sarcoma stem survival outcome synergism therapeutic target therapeutically effective therapy outcome tumor tumor growth tumor microenvironment

项目摘要

ABSTRACT Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality in both men and women. Despite rapid therapeutic advances, the 5-year survival rate of EGFR-mutant NSCLC remains a dismal 16% for the past several decades. In particular, the rapid emergence of resistance to widely used treatments, such as the tyrosine kinase inhibitor (TKI), is the key obstacle to achieving long-term NSCLC patient survival. Further, patients with EGFR mutated tumors fail to respond to immune checkpoint inhibitors (ICIs), leaving them with little to no hope of a long-term remission. Therefore, identifying the molecular determinants of resistance and developing a therapeutic that targets the chemo- and immune-resistant pathways, is the best chance to improve survival rates in NSCLC patients with an EGFR mutation. We hypothesize that MU-CN29, the lead targeted siRNA nanoconjugate, restores sensitivity to tyrosine kinase inhibitors in resistant NSCLC. We further postulate that MU-CN29 will induce a systemic immune response, priming the tumor microenvironment for immunotherapy via ICIs. Therefore, the central objective of this TTNCI proposal is to develop, evaluate, and validate MU-CN29 as an effective therapeutic agent for resistant NSCLC. Our promising in vitro and in vivo experimental results confirmed the crosstalk between the resistance-driving receptor tyrosine kinase AXL and FN14 pathways in drug resistant NSCLC. Additionally, we found that the co-knockdown of both AXL and FN14, using MU-CN29, covalently attached with the dual siRNAs, sensitized the resistant tumors to tyrosine kinase inhibitor (TKI), in vitro and in vivo. To enable translation of MU-CN29 to human trials, in this proposal, we will manufacture the nanoparticles as per FDA guidelines, perform detailed toxicology studies in murine and canine subjects, and evaluate the therapeutic efficacy in clinically relevant animal models. The specific aims of this applications are: (1) Determine MU-CN29 clinical-grade production protocols; (2) Determine the safety and efficacy of MU-CN29 in murine NSCLC models; (3) Establish safety of MU-CN29 in canine cancer patients. The data will validate MU-CN29 nanoparticle platform as a promising strategy to combat drug resistance in NSCLC and catalyze clinical trials in the future.

抽象的非小细胞肺癌（NSCLC）是男性和女性癌症死亡率的主要原因。尽管快速治疗的进步，EGFR突变NSCLC的5年生存率仍然是16％过去几十年。特别是，对广泛使用治疗的抗药性的迅速出现，例如酪氨酸激酶抑制剂（TKI）是实现长期NSCLC患者生存的关键障碍。更远， EGFR突变肿瘤患者无法对免疫检查点抑制剂（ICI）反应长期缓解几乎没有希望。因此，确定抗性的分子决定因素和开发针对化学和免疫途径的治疗性，是最好的机会提高EGFR突变的NSCLC患者的存活率。我们假设MU-CN29，铅靶向siRNA纳米缀合物，恢复了耐药NSCLC中对酪氨酸激酶抑制剂的敏感性。我们进一步假设MU-CN29会引起全身免疫反应，从而启动肿瘤微环境通过ICIS进行免疫疗法。因此，该TTNCI建议的核心目标是开发，评估和验证MU-CN29作为耐药NSCLC的有效治疗剂。我们有希望的体外和体内实验结果证实了阻力驱动受体酪氨酸激酶AXL和耐药NSCLC中的FN14途径。此外，我们发现AXL和FN14的共同敲击，使用与双siRNA共同连接的MU-CN29将抗性肿瘤敏感到酪氨酸激酶抑制剂（TKI），体外和体内。为了使MU-CN29转换为人类试验，在此提案中，我们将根据FDA指南制造纳米颗粒，在鼠和犬类中进行详细的毒理学研究受试者，并评估临床相关动物模型中的治疗功效。这个特定的目的应用是：（1）确定MU-CN29临床级生产方案；（2）确定安全性和 MU-CN29在鼠NSCLC模型中的功效；（3）在犬类癌患者中建立MU-CN29的安全性。数据将验证MU-CN29纳米颗粒平台，作为打击耐药性的有前途的策略 NSCLC和将来催化临床试验。