Novel Targeted Nanomedicine Delivering MicroRNA-30-5p ReplacementTherapy for Multi-drug Resistant Cancer Treatment

新型靶向纳米药物为多重耐药癌症治疗提供 MicroRNA-30-5p 替代疗法

基本信息

批准号：
10203869
负责人：
Anthony D Saleh
金额：
$ 100万
依托单位：
MIRECULE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-22 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10203869
关键词：
3-Dimensional Adhesions Animals Biodistribution Biological Blood Cells Cetuximab Chemicals Chemistry Cisplatin Clinical Clinical Data Clinical Trials Combined Modality Therapy Cytotoxic Chemotherapy DNA Sequence Alteration Data Development Disease Dose Drug resistance Effectiveness Encapsulated Epidermal Growth Factor Receptor Extracellular Matrix Family Formulation Gene Deletion Genes Genomics Goals Growth Factor Overexpression Growth Factor Receptors Half-Life Head and Neck Neoplasms Head and Neck Squamous Cell Carcinoma IGF1R gene Injections Investments Legal patent Link Luciferases Malignant Neoplasms Maximum Tolerated Dose Measurement Measures Messenger RNA MicroRNAs Modeling Mus Oligonucleotides Oncogenes Oncogenic Oropharyngeal Head and Neck Squamous Cell Carcinoma Orphan Drugs Outcome Pathway interactions Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Population Privatization Production Rattus Replacement Therapy Resistance Rodent Model Sampling Signal Pathway Small Business Innovation Research Grant Solid Neoplasm Sum Survival Rate TFRC gene Technology Testing Therapeutic Tissues Toxic effect Toxicology Transcript Tumor Tissue Up-Regulation anti-PD1 antibodies anti-PD1 therapy base cancer cell cancer therapy clinical development cytokine cytotoxic drug discovery effective therapy efficacy study improved in vivo in vivo Model innovation lipid nanoparticle manufacturing scale-up meetings microRNA replacement therapy migration mouse model multidrug resistant cancer nanomedicine nanoparticle delivery novel nuclease nucleic acid-based therapeutics overexpression patient derived xenograft model pharmacokinetics and pharmacodynamics process optimization response scale up small molecule standard of care survival outcome targeted treatment therapeutic miRNA tumor tumor heterogeneity tumor progression

项目摘要

Abstract: In this phase 2 SBIR application, miRecule proposes to develop a microRNA-based therapeutic mimic of miR- 30-5p (miRecule candidate MC-30) for the treatment of multi-drug resistant (MDR) cancers. Head and Neck Squamous Cell Carcinoma (HNSCC) is the 6th most common form of cancer. Greater than half of patients present with late stage III or IV disease, with an average 5-year survival rate of ~40%. HNSCC tumors have high levels of genetic mutations leading to high tumor heterogeneity and drug resistance. miR-30-5p expression is widely repressed in tumor tissues and MIR30 gene deletion is observed in ~30% of HNSCCs. Loss of miR-30- 5p expression correlates with poor survival outcome in 100% of Oropharyngeal HNSCC patients (OPSCC), which represents our initial clinical population. miR-based therapeutics offer a disruptive approach for treatment of MDR cancer by targeting both primary oncogenic pathways and mechanisms of intrinsic or acquired resistance. EGFR targeted therapy is often compensated for by overexpression of growth factor receptors (GFRs) MET and IGF1R. However, we have discovered that miR-30-5p simultaneously targets and repress all three of these GFRs. The rationale for miR-30-5p replacement therapy is that it will be superior in its ability to treat heterogeneous late-stage HNSCC due to its ability to regulate not only EGFR, but also MET, IGF- 1R, and over two dozen other mRNAs confirmed to be deregulated in tumor tissue and associated with proliferation, adhesion, migration, extracellular matrix remodeling, and differentiation. In phase 1 of our SBIR, we developed a chemically-modified mimic of miR-30-5p with >1000x improved nuclease stability and 5X activity in HNSCC models compared to the natural microRNA. We also demonstrated simultaneous inhibition of a dozen critical oncogenes in HNSCC with evidence that our mimic to can overcome cisplatin and EGFR-related drug resistance. We also demonstrated that of our clinically validated LNP formulation, which targets solid tumors via an scFv against the transferrin receptor (TfR), overcomes the challenge of delivery to cancer cells by having activity at a low dose of 1 mg/kg in vivo. This was demonstrated in both biodistribution studies and four different in vivo models of HNSCC that all showed strong sensitivity to MC-30. In this Phase II SBIR study, we propose to: 1) Characterized PK/PD and non-GLP Tox studies of MC-30. 2) Create a compelling data package that demonstrates dose-dependent efficacy of MC-30 in syngeneic and PDX models. 3) Demonstrate the competitive advantage of MC-30 over approved cisplatin, cetuximab, and anti-PD-1 therapies with potential for combination use. 4) Validate our proposed clinical population of OPSCC patients in a mini ex vivo clinical trial. 5) Optimize scale-up, manufacturing, and CMC release tests for MC-30. The sum of these studies will support filing an orphan drug application, enable our pre-IND meeting, guide our clinical development, and validate outside investment in MC-30.

抽象的：在此阶段2 SBIR应用中，Mirecule提议开发基于microRNA的mim-的治疗模仿 30-5p（mirecule候选MC-30）用于治疗多药耐药（MDR）癌症。头和脖子鳞状细胞癌（HNSCC）是癌症的第六大形式。大于一半的患者存在晚期III或IV疾病，平均5年生存率约为40％。 HNSCC肿瘤高导致高肿瘤异质性和耐药性的遗传突变水平。 miR-30-5p表达是在HNSCC中，观察到在肿瘤组织中广泛抑制和miR30基因缺失。 mir-30-损失 5p表达与100％的口咽HNSCC患者（OPSCC）的生存结果差相关，代表我们最初的临床人群。基于miR的治疗剂为通过靶向固有或固有的原始致癌途径和机制来治疗MDR癌获得的阻力。 EGFR靶向治疗通常通过生长因子的过表达来补偿受体（GFRS）MET和IGF1R。但是，我们发现miR-30-5p同时定位压制所有这三个GFR。 miR-30-5p替代疗法的基本原理是它在其上将是优越的由于它不仅可以调节EGFR，而且要满足IGF- 1R，另外二十多个mRNA证实在肿瘤组织中受管制，并与增殖，粘附，迁移，细胞外基质重塑和分化。在我们的Sbir的第一阶段中，我们开发了一种化学改性的miMIM miR-30-5p，> 1000 x提高了核酸酶稳定性和5x活性在HNSCC模型中，与天然microRNA相比。我们还证明了十几个 HNSCC中的关键癌基因有证据表明我们的模仿可以克服顺铂和EGFR相关的药物反抗。我们还证明了我们经过临床验证的LNP公式，该公式针对实体瘤针对转铁蛋白受体（TFR）的SCFV通过具有在体内低剂量1 mg/kg的活性。这在生物分布研究和四个 HNSCC的体内模型不同，所有模型均显示出对MC-30的强烈敏感性。在此II阶段SBIR研究中，我们建议：1）表征了PK/PD和MC-30的非GLP TOX研究。 2）创建一个引人入胜的数据包装证明了MC-30在同基因和PDX模型中的剂量依赖性功效。 3）演示 MC-30比批准的顺铂，西妥昔单抗和抗PD-1疗法的竞争优势用于组合使用。 4）在小体内临床中验证我们提出的OPSCC患者的临床人群审判。 5）优化MC-30的扩大，制造和CMC发布测试。这些研究的总和将支持提交孤儿毒品申请，启用我们的预定会议，指导我们的临床发展以及验证MC-30的外部投资。