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

• 批准号: 10011679
• 负责人: Robert F Place
• 金额: $ 100万
• 依托单位: MIRECULE, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-22 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10011679
• 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; pharmacokinetics and pharmacodynamics; process optimization; response; scale up; small molecule; standard of care; survival outcome; targeted treatment; therapeutic miRNA; tumor; tumor heterogeneity; tumor progression

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.

摘要： 在这项2期SBIR申请中，miRecule提出开发一种基于microRNA的miR-125治疗模拟物。 30- 5 p（miRecule候选MC-30）用于治疗多药耐药（MDR）癌症。头颈 鳞状细胞癌（HNSCC）是第六种最常见的癌症。超过一半的患者 晚期III或IV期疾病，平均5年生存率约为40%。HNSCC肿瘤具有高 基因突变水平导致高肿瘤异质性和耐药性。miR-30- 5 p的表达是 在肿瘤组织中广泛抑制，在约30%的HNSCC中观察到MIR 30基因缺失。miR-30缺失- 5 p表达与100%的口咽HNSCC患者（OPSCC）的不良生存结局相关， 这代表了我们最初的临床人群。基于miR的疗法提供了一种破坏性的方法， 通过靶向主要致癌途径和内源性或内源性肿瘤的机制治疗MDR癌症 获得性抵抗EGFR靶向治疗通常通过生长因子的过表达来补偿 受体（GFR）MET和IGF 1 R。然而，我们已经发现miR-30- 5 p同时靶向和 抑制这三种GFRs miR-30- 5 p替代疗法的基本原理是，它在其治疗中具有上级优势。 治疗异质性晚期HNSCC的能力，因为其不仅能够调节EGFR，而且能够调节MET、IGF-1， 1 R和超过20种其他mRNA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， 我们开发了一种化学修饰的miR-30- 5 p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相比。我们还同时抑制了12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 阻力我们还证明了我们的临床验证的LNP制剂，其通过以下途径靶向实体瘤： 抗转铁蛋白受体（TfR）的scFv克服了递送至癌细胞的挑战， 在体内以1 mg/kg的低剂量具有活性。这在生物分布研究和四项 HNSCC的不同体内模型均显示对MC-30的强敏感性。在这项II期SBIR研究中， 我们建议：1）MC-30的特征化PK/PD和非GLP Tox研究。2)创建引人注目的数据 该软件包证明了MC-30在同基因和PDX模型中的剂量依赖性疗效。3)证明 MC-30相对于获批顺铂、西妥昔单抗和抗PD-1治疗的竞争优势， 用于组合使用。4)在一项小型离体临床试验中， 审判5)优化MC-30的规模放大、生产和CMC放行测试。这些研究的总和将 支持提交孤儿药申请，支持我们的IND前会议，指导我们的临床开发， 验证MC-30的外部投资。