RNA Therapeutics for Targeted Treatment of Colon Cancer

用于结肠癌靶向治疗的 RNA 疗法

基本信息

批准号：
9277427
负责人：
BIN GUO
金额：
$ 34.17万
依托单位：
UNIVERSITY OF HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-19 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9277427
关键词：
Adverse effects Affect Animal Cancer Model Antibodies Binding Biodistribution Biophysics Bypass Calcitriol Cancer Etiology Catalytic RNA Cells Cessation of life Chemicals Clinical Clinical Research Colon Carcinoma Colorectal Cancer Drug Kinetics Drug usage Epigenetic Process Fluorouracil GPA33 gene Gastroenterology Gene Silencing Glycoprotein A33 Goals Growth Half-Life Hypercalcemia Immune response In Vitro Injection of therapeutic agent Interferons Leucovorin Liver Lung Malignant Neoplasms Mediator of activation protein Metabolic Clearance Rate Metastasis Suppression MicroRNAs Molecular Motor Mus Nanotechnology Natural Immunity Nature Neoplasm Metastasis Nude Mice Organ Pharmacology Prevention Primary Neoplasm RNA Regimen Research Personnel Research Project Grants Resistance Risk Salts Small Interfering RNA Structure TACSTD1 gene Tail Testing Therapeutic Therapeutic Effect Thermodynamics Time Tissues Toxic effect Transfection Tumor Antigens Tumor Suppression Urea Veins Vitamin D Xenograft Model Xenograft procedure aptamer arm base cancer cell cancer diagnosis cancer therapy cancer type capecitabine chemotherapy colon cancer cell line cytokine effective therapy epigenetic regulation gene function growth promoting activity histone demethylase improved in vivo innovation irinotecan nano nanoparticle novel novel strategies novel therapeutic intervention novel therapeutics oxaliplatin prevent public health relevance response scaffold targeted delivery targeted treatment therapeutic miRNA therapeutic siRNA therapeutic target treatment effect treatment strategy tumor

项目摘要

DESCRIPTION: There is an urgent need to develop novel strategies for treatment of advanced and metastatic colon cancers since they have limited responses to conventional chemotherapies. In this proposal, we will apply a new RNA-based strategy to deliver therapeutic miRNA and siRNA for targeted colon cancer therapy. We (Bin Guo's group) have recently found that miR-627 is induced by calcitriol and acts as a key mediator of calcitriol's suppression of colon cancer (Gastroenterology, 2013, 145(2):437-46). We have further demonstrated that miR-627 targets histone demethylase JMJD1A, an epigenetic regulator that has growth-promoting activity. Both miR-627 and JMJD1A-targeting siRNA can significantly inhibit colon cancer growth in vitro and in vivo (nude mice xenografts). We hypothesize that if we could employ targeted delivery of miR-627 or siRNA to directly inhibit JMJD1A, it would be possible to bypass the side effects associated with calcitriol and achieve tumor suppression. The co-investigator's (Peixuan Guo) group has discovered an unusually stable phi29 pRNA three-way junction (3WJ) motif that can be used as a scaffold to construct multivalent RNA nanoparticles with very high chemical and thermodynamic stability (Nature Nanotechnology, 2011, 6:658-67; Nano Today, 2012, 7:245- 257). The resulting RNA nanoparticles harbor different siRNA, miRNA, and cancer targeting module (such as RNA aptamer) that retain their folding and independent functionalities for gene silencing and cancer targeting both in vitro and in vivo. These RNA nanoparticles are resistant to denaturation in 8 M urea and do not dissociate at ultra-low concentrations in vitro and in vivo. Systemic injection into the tail-vein of mice has revealed that they remain intact and strongly bind to cancers without accumulating in the liver, lungs or other vital organs. This nanotechnology approach has enhanced the half-life of the RNA nanoparticles by 10-fold compared to the bare siRNA. The 3WJ-pRNA nanoparticles are non-toxic and display favorable pharmacological profiles that include biodistribution, pharmacokinetics (stability, half-life, and clearance rate), and undetectable immune responses (Molecular Therapy, 2011, 19:1312-22). The goal of this research project is to construct multivalent nanoparticles composed of RNA, to obtain enhanced or synergistic therapeutic effects for the treatment of colon cancer. We will conjugate (1) EpCAM aptamer for targeting tumor antigen EpCAM or A33 scFv for specific binding to colon cancer specific cell surface antigen A33 resulting in the internalization of RNA nanoparticles into the colon cancer cells; and (2) therapeutic modules, miR-627 and/or JMJD1A siRNA, to silence the expression of JMJD1A. Emphasis will be on specific tumor targeting and efficiency of gene silencing in vivo for treatment of primary tumor as well as suppression of metastasis. We will systematically evaluate the pharmacological profiles concerning biodistribution, pharmacokinetics, and immune responses (antibody induction, and interferon, toll-like and innate immunity, PKR effect, and cytokine induction) of this innovative RNA delivery platform. The combined effect of the multivalent RNA nanoparticles for enhancing chemotherapy will be evaluated. We are confident that our RNA-based approach will result in an innovative therapeutic for colon cancer.

描述：迫切需要开发治疗晚期和转移性结肠癌的新策略，因为它们对传统化疗的反应有限。在本提案中，我们将应用一种新的基于 RNA 的策略来为靶向结肠提供治疗性 miRNA 和 siRNA。我们（郭斌课题组）最近发现 miR-627 是由骨化三醇诱导的，并且是骨化三醇抑制结肠癌的关键介质（胃肠病学， 2013, 145(2):437-46）我们进一步证明 miR-627 靶向组蛋白去甲基化酶 JMJD1A，这是一种具有生长促进活性的表观遗传调节因子，miR-627 和 JMJD1A 靶向 siRNA 均可显着抑制结肠癌生长。体外和体内（裸鼠异种移植物）我们发现，如果我们能够采用 miR-627 或 miR-627 的靶向递送。 siRNA 直接抑制 JMJD1A，将有可能绕过与骨化三醇相关的副作用并实现肿瘤抑制。共同研究人员（郭培轩）小组发现了一种异常稳定的 phi29 pRNA 三向连接（3WJ）基序。用作构建多价RNA纳米粒子的支架，具有非常高的化学和热力学稳定性（Nature Nanotechnology，2011，6：658-67； Nano Today, 2012, 7:245-257) 由此产生的 RNA 纳米粒子包含不同的 siRNA、miRNA 和癌症靶向模块（例如 RNA 适体），这些模块保留了其折叠和独立的功能，用于体外和体内的基因沉默和癌症靶向。这些 RNA 纳米粒子在 8 M 尿素中能抵抗变性，并且在体外和体内注射超低浓度时不会解离。老鼠的尾静脉显示它们保持完整并且与裸 siRNA 相比，这种纳米技术方法可与癌症牢固结合，而不会在肝脏、肺或其他重要器官中积累。3WJ-pRNA 纳米颗粒无毒且无毒。良好的药理学特征，包括生物分布、药代动力学（稳定性、半衰期和清除率）和不可检测的免疫反应（分子疗法，2011， 19:1312-22）该研究项目的目标是构建由RNA组成的多价纳米颗粒，以获得针对结肠癌治疗的增强或协同治疗效果。 A33 scFv 与结肠癌特异性细胞表面抗原 A33 特异性结合，导致 RNA 纳米颗粒内化到结肠癌细胞中；以及 (2) 治疗模块， miR-627 和/或 JMJD1A siRNA，以沉默 JMJD1A 的表达，重点是体内基因沉默治疗原发性肿瘤以及抑制转移的特异性肿瘤靶向和效率。这种创新 RNA 递送的生物分布、药代动力学和免疫反应（抗体诱导、干扰素、Toll 样免疫和先天免疫、PKR 效应和细胞因子诱导）我们将评估多价 RNA 纳米粒子增强化疗的综合效果，我们相信我们的基于 RNA 的方法将产生一种创新的结肠癌治疗方法。