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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.

产品说明：由于晚期和转移性结肠癌对常规化疗的反应有限，因此迫切需要开发用于治疗晚期和转移性结肠癌的新策略。在这项提案中，我们将应用一种新的基于RNA的策略来递送治疗性miRNA和siRNA用于靶向结肠癌治疗。我们（郭斌小组）最近发现miR-627由钙三醇诱导，并作为钙三醇抑制结肠癌的关键介导剂（胃肠病学，2013，145（2）：437 - 46）。我们进一步证明了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。靶向miR-627和JMJD1A的siRNA在体外和体内（裸鼠异种移植物）均能显著抑制结肠癌生长。我们假设，如果我们能够采用靶向递送miR-627或siRNA来直接抑制JMJD1A，则有可能绕过与骨化三醇相关的副作用并实现肿瘤抑制。共同研究者（Peixuan Guo）的小组已经发现了异常稳定的phi29 pRNA三向连接（3WJ）基序，其可以用作支架以构建具有非常高的化学和热力学稳定性的多价RNA纳米颗粒（Nature Nanotechnology，2011，6：658 - 67; Nano Today，2012，7：245 - 257）。所得的RNA纳米颗粒具有不同的siRNA、miRNA和癌症靶向模块（如RNA适体），其保留了它们的折叠和独立功能，用于体外和体内的基因沉默和癌症靶向。这些RNA纳米颗粒在8 M尿素中抗变性，并且在体外和体内在超低浓度下不解离。全身注射到小鼠的尾静脉中显示，它们保持完整，与癌症强烈结合，而不会在肝脏，肺部或其他重要器官中积累。与裸SiRNA相比，这种纳米技术方法将RNA纳米颗粒的半衰期延长了10倍。3WJ-pRNA纳米颗粒是无毒的，并且显示出有利的药理学特征，包括生物分布、药代动力学（稳定性、半衰期和清除率）和不可检测的免疫应答（Molecular Therapy，2011，19：1312 - 22）。本研究项目的目标是构建由RNA组成的多价纳米颗粒，以获得增强或协同治疗结肠癌的疗效。我们将缀合（1）EpCAM适体，其用于靶向肿瘤抗原EpCAM或A33 scFv，其用于特异性结合结肠癌特异性细胞表面抗原A33，导致RNA纳米颗粒内化到结肠癌细胞中;和（2）治疗模块，miR-627和/或JMJD1A siRNA，以沉默JMJD1A的表达。重点将放在特定的肿瘤靶向和效率的基因沉默在体内治疗原发性肿瘤以及抑制转移。我们将系统地评估这个创新RNA递送平台的生物分布、药代动力学和免疫反应（抗体诱导、干扰素、toll样和先天免疫、PKR效应和细胞因子诱导）的药理学特征。将评估多价RNA纳米颗粒用于增强化疗的组合效果。我们相信，我们基于RNA的方法将为结肠癌提供一种创新的治疗方法。