MULTI-TARGETED RNAI THERAPEUTICS FOR GLIOBLASTOMA MULTIFORME (GBM)

多形性胶质母细胞瘤 (GBM) 的多靶点 RNAI 治疗

• 批准号: 7910904
• 负责人: Patrick Y Lu
• 金额: $ 26.93万
• 依托单位: SIRNAOMICS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-02 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7910904
• 关键词: Accounting; Adult; Apoptosis; Applications Grants; Avastin; Basic Science; Biopsy; Brain; Cell Culture Techniques; Cell Line; Cell Proliferation; Cells; Central Nervous System Neoplasms; Characteristics; Cleaved cell; Clinical Research; Computer Simulation; DNA Repair Enzymes; DNA Sequence Rearrangement; Development; Diagnosis; Disease; Down-Regulation; Drug Formulations; Epidermal Growth Factor Receptor; Erlotinib; Exhibits; Gefitinib; Gene Expression; Gene Silencing; Gene Targeting; Genes; Genetic; Glioblastoma; Glioma; Hand; Histidine; Histopathology; Human; In Vitro; Incidence; Investigation; Lipids; Liposomes; Lysine; MMP2 gene; MMP9 gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Matrix Metalloproteinases; Measures; Mediating; Messenger RNA; Modeling; Molecular Abnormality; Monoclonal Antibodies; Mus; Mutation; Nature; Neoplasms; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Phase; Phenotype; Polymers; Protocols documentation; RNA Interference; RNA-Induced Silencing Complex; Radiation therapy; Regimen; Resistance; Safety; Series; Signal Pathway; Signal Transduction Pathway; Small Interfering RNA; Survival Rate; System; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Transforming Growth Factors; Tyrosine Kinase Inhibitor; United States; Vascular Endothelial Growth Factors; Xenograft procedure; angiogenesis; base; beta-Glucosidase Stimulating Protein; chemotherapy; combat; cytokine; glioma cell line; in vivo; inhibitor/antagonist; nanoparticle; neoplastic; neoplastic cell; new therapeutic target; novel therapeutics; outcome forecast; overexpression; preclinical study; public health relevance; receptor; response; small molecule; technology development; temozolomide; therapeutic target; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Glioblastoma Multiforme (GBM), the most common brain cancer of adults, is among the most aggressive and deadly of neoplasm (WHO grade IV), and is accounted for more than 21% of all primary brain and CNS tumors. The annual incidence of GBM in the United States is 3.01 per 100,000 and is an incurable cancer with a median survival of approximately 12 months from diagnosis. Despite decades of intensive surgical treatment, chemotherapy, radiotherapy, and tremendous basic science and clinical research focused on combating this disease, the prognosis remains virtually unchanged, with survival rates still measured in months. The current genetic understanding of GBM has led to the identification of crucial intracellular molecules and their associated signaling pathways as potential therapeutic targets. We are taking the advantage of RNA interference (RNAi) technology for development of the targeted therapeutics. Three small interfering RNA (siRNA) cocktails targeting EGFR-VEGF-AGT, or EGFR-VEGF-MMP9, or EGFR-VEGF-TGF respectively, will be packaged with Histidine and Lysine polymer (HKP) and Saposin C DOPS liposome nanoparticles for treatment of GBM. The antitumor efficacy of these siRNA nanoparticle drugs will be evaluated with human glioma cell lines U87 and murine glioma cells SMA-560 cell tumor models. We will also characterize the HKP and SapC-DOPS nanoparticle systems with the most potent siRNA cocktail and selected a nanoparticle-siRNA cocktail formulation for GBM treatment with the favorable efficacy and safety profile. Lastly, we will evaluate combined regimen of the siRNA cocktail A with TMZ, or cocktail B and C with Avastin, using the U87 and SMA-560 cell tumor models, with the best nanoparticle delivery formulation. A novel therapeutic protocol will be ready for further preclinical study to support a Phase II grant application. PUBLIC HEALTH RELEVANCE: Glioblastoma Multiforme (GBM), the most common brain cancer of adults, is among the most aggressive and deadly of neoplasm (WHO grade IV), and is accounted for more than 21% of all primary brain and CNS tumors. The annual incidence of GBM in the United States is 3.01 per 100,000 and is an incurable cancer with a median survival of approximately 12 months from diagnosis. Despite decades of intensive surgical treatment, chemotherapy, radiotherapy, and tremendous basic science and clinical research focused on combating this disease, the prognosis remains virtually unchanged. We are proposing here to take the advantage of RNA interference (RNAi) technology for development of a novel targeted therapeutic with three small interfering RNA (siRNA) cocktails targeting EGFR-VEGF-AGT, or EGFR-VEGF-MMP9, or EGFR-VEGF-TGF respectively. Two nanoparticle systems, HKP and SapC-DOPS, will be applied with the most potent siRNA cocktail and in combination with the small molecule antagonist drug (TMZ) and monoclonal antibody drug (Avastin) for their antitumor efficacy using both xenograft (U87 cell) and syngeneic (SMA-560 cell) mouse tumor models.

描述(申请人提供)：多形性胶质母细胞瘤(GBM)是成人最常见的脑癌，是最具侵袭性和致命性的肿瘤之一(WHO IV级)，占所有原发脑肿瘤和中枢神经系统肿瘤的21%以上。在美国，GBM的年发病率为3.01/10万，是一种无法治愈的癌症，确诊后中位生存期约为12个月。尽管几十年来密集的外科治疗、化疗、放射治疗以及专注于抗击这种疾病的大量基础科学和临床研究，但预后几乎没有变化，存活率仍以月为单位衡量。目前对GBM的遗传学理解导致了关键的细胞内分子及其相关的信号通路被确定为潜在的治疗靶点。我们正在利用RNA干扰(RNAi)技术来开发靶向疗法。三种针对EGFR-VEGF-AGT、EGFR-VEGF-MMP9或EGFR-VEGF-TGF的小干扰RNA(SiRNA)鸡尾酒将分别与组氨酸和赖氨酸聚合物(HKP)和皂苷C DOPS脂质体纳米粒一起包装，用于治疗GBM。这些siRNA纳米药物的抗肿瘤效果将通过人脑胶质瘤细胞系U87和小鼠脑胶质瘤细胞SMA-560细胞肿瘤模型进行评估。我们还将用最有效的siRNA鸡尾酒对HKP和SapC-DOPS纳米颗粒系统进行表征，并选择具有良好疗效和安全性的纳米颗粒-siRNA鸡尾酒配方用于治疗GBM。最后，我们将使用U87和SMA-560细胞肿瘤模型，评价siRNA鸡尾酒A与TMZ或鸡尾酒B和C与阿瓦斯丁的联合方案，并获得最佳纳米颗粒递送配方。一种新的治疗方案将为进一步的临床前研究做好准备，以支持第二阶段拨款申请。 公共卫生相关性：多形性胶质母细胞瘤(GBM)是成人最常见的脑癌，是最具侵袭性和致命性的肿瘤之一(WHO IV级)，占所有原发脑肿瘤和中枢神经系统肿瘤的21%以上。在美国，GBM的年发病率为3.01/10万，是一种无法治愈的癌症，确诊后中位生存期约为12个月。尽管几十年来密集的手术治疗、化疗、放射治疗以及大量的基础科学和临床研究都集中在对抗这种疾病上，但预后几乎没有变化。我们建议利用RNA干扰(RNAi)技术开发一种新的靶向治疗方法，即三种针对EGFR-VEGF-AGT或EGFR-VEGF-MMP9或EGFR-VEGF-TGF的小干扰RNA(SiRNA)鸡尾酒。两种纳米粒子系统HKP和SapC-DOPS将与最有效的siRNA鸡尾酒一起应用，并与小分子拮抗剂药物(TMZ)和单抗药物(阿瓦斯丁)结合使用，通过使用异种(U87细胞)和同基因(SMA-560细胞)小鼠肿瘤模型来研究其抗肿瘤效果。