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：在这个 2 期 SBIR 应用中，miRecule 提议开发一种基于 microRNA 的 miR-治疗模拟物 30-5p（miRecule 候选药物 MC-30）用于治疗多重耐药 (MDR) 癌症。头部和颈部鳞状细胞癌 (HNSCC) 是第六种最常见的癌症。超过一半的患者患有晚期 III 期或 IV 期疾病，平均 5 年生存率约为 40%。 HNSCC 肿瘤具有高导致高肿瘤异质性和耐药性的基因突变水平。 miR-30-5p 表达为 MIR30 基因在肿瘤组织中被广泛抑制，约 30% 的 HNSCC 中观察到 MIR30 基因缺失。 miR-30- 丢失 5p 表达与 100% 口咽部 HNSCC 患者 (OPSCC) 的不良生存结果相关，这代表了我们最初的临床人群。基于 miR 的疗法提供了一种颠覆性方法通过针对主要致癌途径和内在或机制来治疗 MDR 癌症获得性抵抗。 EGFR 靶向治疗通常通过生长因子的过度表达来补偿受体 (GFR) MET 和 IGF1R。然而，我们发现 miR-30-5p 同时靶向和抑制所有这三种 GFR。 miR-30-5p 替代疗法的基本原理是，它在以下方面更优越：能够治疗异质性晚期 HNSCC，因为它不仅能够调节 EGFR，还能够调节 MET、IGF- 1R 和超过两打其他 mRNA 已被证实在肿瘤组织中失调并与增殖、粘附、迁移、细胞外基质重塑和分化。在 SBIR 的第一阶段，我们开发了一种经过化学修饰的 miR-30-5p 模拟物，其核酸酶稳定性提高了 1000 倍，活性提高了 5 倍在 HNSCC 模型中与天然 microRNA 进行比较。我们还证明了同时抑制十几个 HNSCC 中的关键癌基因，有证据表明我们的模拟物可以克服顺铂和 EGFR 相关药物反抗。我们还证明了经过临床验证的 LNP 制剂，该制剂通过以下方式靶向实体瘤：针对转铁蛋白受体 (TfR) 的 scFv 通过具有 1 mg/kg 的低剂量体内活性。这在生物分布研究和四项研究中得到了证明不同的 HNSCC 体内模型均表现出对 MC-30 的强敏感性。在这项 II 期 SBIR 研究中，我们建议：1) MC-30 的 PK/PD 和非 GLP Tox 特征研究。 2）创建引人注目的数据该软件包展示了 MC-30 在同基因和 PDX 模型中的剂量依赖性功效。 3）展示 MC-30 相对于已批准的顺铂、西妥昔单抗和抗 PD-1 疗法的竞争优势具有潜力组合使用。 4) 在小型离体临床中验证我们提出的 OPSCC 患者临床群体审判。 5) 优化MC-30的放大、制造和CMC释放测试。这些研究的总和将支持提交孤儿药申请，启动我们的 IND 前会议，指导我们的临床开发，以及验证 MC-30 的外部投资。