A Novel Targeted Nanomedicine Delivering MicroRNA-30-5p Replacement Therapy for Multi-drug Resistant Cancer Treatment

一种新型靶向纳米药物，为多重耐药癌症治疗提供 MicroRNA-30-5p 替代疗法

• 批准号: 9409281
• 负责人: Esther H Chang
• 金额: $ 29.93万
• 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 2019-08-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9409281
• 关键词: Adhesions; Adverse effects; Animals; Biological; Biopsy; Blood Chemical Analysis; Body Weight; Cell Line; Cell Maintenance; Cells; Cetuximab; Chemicals; Cisplatin; Clinical; DNA Sequence Alteration; Disease; Dose; Drug resistance; Encapsulated; Ensure; Epidermal Growth Factor Receptor; Exhibits; Extracellular Matrix; FDA approved; Family; Formulation; Future; Gene Amplification; Gene Deletion; Gene Expression; Gene Targeting; Genes; Genomics; Goals; Growth Factor Receptors; Half-Life; Head and Neck Neoplasms; Head and Neck Squamous Cell Carcinoma; Hematology; Histopathology; IGF1R gene; Immunoglobulin Fragments; Implant; In Vitro; Kinetics; Lead; Liposomes; Luciferases; Malignant Epithelial Cell; Malignant Neoplasms; Measures; Messenger RNA; Metastatic to; MicroRNAs; Modeling; Multi-Drug Resistance; Mus; Neoplasm Metastasis; Normal tissue morphology; Nucleic Acids; Oncogenic; Organ; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Pre-Clinical Model; Preparation; Proliferating; Regimen; Replacement Therapy; Reporter; Repression; Resistance; Resistance development; Signal Pathway; Signal Transduction; Site; Small Business Innovation Research Grant; Surface; Survival Rate; System; TFRC gene; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Tumor Tissue; Xenograft procedure; base; cancer cell; cancer therapy; cell killing; chemotherapy; combat; cytotoxic; design; drug candidate; drug discovery; effective therapy; improved; in vivo; innovation; knock-down; migration; molecular marker; mouse model; nanomedicine; novel; nuclease; overexpression; potential biomarker; pre-clinical; receptor mediated endocytosis; response; safety study; small molecule; standard of care; targeted treatment; tumor; tumor growth; tumor heterogeneity; tumor progression; uptake

Abstract: In this 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. miR-based therapeutics offer a disruptive MDR cancer treatment by targeting both the primary oncogenic pathways and potentially suppressing mechanisms of intrinsic or acquired resistance. EGFR targeted therapy is often resisted by overexpression of the compensating growth factor receptors (GFRs) MET and IGF1R. We have made the novel discovery that miR-30-5p can target and repress all three of these GFRs. The rationale for our design is that a miR-30-5p mimic 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 over-proliferation, adhesion, migration, extracellular matrix remodeling, and differentiation. Our early study shows that a chemically modified mimic of miR-30-5p, exhibiting significantly improved efficacy over the biological microRNA, was effective at inhibiting tumor growth in vivo in a preclinical model of HNSCC. A significant hurdle for nucleic acid therapeutics is a lack of an efficient means of delivering them specifically to target cancer cells, especially at the metastatic stage. To overcome this obstacle, we employ two unique strategies. First, our chemically modified mimic of miR-30-5p has vastly improved nuclease stability and activity, decreasing the amount of mimic that needs to be present in the cell to produce the desired effect, and extending the duration of response. Second, our mimics are encapsulated in a clinically validated tumor- targeted liposomal nanodelivery system (scL). The nanocomplex carries an scFv antibody fragment against the transferrin receptor (TfR), which is up-regulated on the surface of most cancer cells and triggers uptake via receptor-mediated endocytosis. In this Phase I SBIR study we aim to we will characterize the half-life of our lead nuclease-stabilized mimic in HNSCC cells, targeting of multiple oncogenic mRNAs and signaling pathways, and test our hypothesis that it can more effectively combat drug resistance in vitro (Aim 1). We will test this mimic in a cetuximab and cisplatin-resistant orthotopic xenograft mouse model of HNSCC and compare directly with standard of care cisplatin and cetuximab. We will also assess potential toxicity and off- target effects. (AIM2) Successful completion of these studies will demonstrate the feasibility of MC-30 as a drug candidate and dosing regimen to be used in future PK, TOX, ADME, and other animal studies as required for an IND package. Once FDA approved and commercially available MC-30 will offer an effective treatment of MDR HNSCC and perhaps other cancers for which there are currently no treatment options.

摘要： 在这项SBIR申请中，miRecule提出开发一种基于microRNA的miR-30- 5 p治疗模拟物。 本发明涉及用于治疗多药耐药（MDR）癌症的微分子候选物MC-30。头颈部鳞状 细胞癌（HNSCC）是第六种最常见的癌症。超过一半的患者出现晚期 III或IV期疾病，平均5年生存率约为40%。HNSCC肿瘤具有高水平的遗传 突变导致高肿瘤异质性和耐药性。miR-30- 5 p表达被广泛抑制 在肿瘤组织中，在约30%的HNSCC中观察到MIR 30基因缺失。基于miR的疗法提供了一种 通过靶向主要致癌途径和潜在的 抑制内在或获得性抗性的机制。EGFR靶向治疗通常受到以下因素的抵制： 补偿生长因子受体（GFR）MET和IGF 1 R的过表达。我们把小说 发现miR-30- 5 p可以靶向并抑制所有这三种GFR。我们设计的基本原理是， miR-30- 5 p模拟物在其治疗异质性晚期HNSCC的能力方面将是上级的，这是由于其能够 不仅调节EGFR，还调节MET、IGF-1 R和其他20多种被证实失调的mRNA 在肿瘤组织中，与过度增殖、粘附、迁移、细胞外基质重塑和 分化我们的早期研究表明，miR-30- 5 p的化学修饰模拟物，表现出显著的 在临床前研究中，与生物microRNA相比， HNSCC模型。 核酸治疗的一个重要障碍是缺乏特异性递送它们的有效手段 靶向癌细胞，特别是在转移阶段。为了克服这一障碍，我们采用了两种独特的 战略布局首先，我们化学修饰的miR-30- 5 p模拟物极大地提高了核酸酶稳定性， 活性，减少细胞中产生所需效果所需的模拟物的量，以及 延长响应时间。其次，我们的模拟物被包裹在一个临床验证的肿瘤中- 靶向脂质体纳米递送系统（scL）。该纳米复合物携带抗HLA-I的scFv抗体片段， 转铁蛋白受体（TfR）在大多数癌细胞表面上调，并通过 受体介导的内吞作用。在这项I期SBIR研究中，我们的目标是描述我们的药物的半衰期。 在HNSCC细胞中引导核酸酶稳定模拟物，靶向多种致癌mRNA和信号传导 途径，并测试我们的假设，即它可以更有效地对抗体外耐药性（目的1）。我们将 在HNSCC西妥昔单抗和顺铂抗性原位异种移植小鼠模型中测试该模拟物， 直接与标准治疗顺铂和西妥昔单抗进行比较。我们还将评估潜在的毒性和关闭- 目标效应。（目标2）这些研究的成功完成将证明MC-30作为一种 根据需要，在未来PK、TOX、ADME和其他动物研究中使用的候选药物和给药方案 一个IND包裹。一旦FDA批准和商业化，MC-30将提供有效的治疗， MDR HNSCC和目前没有治疗选择的其他癌症。