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：迫切需要制定新的策略来治疗高级和转移性结肠癌，因为它们对常规化学疗法的反应有限。在此提案中，我们将采用一种新的基于RNA的策略来提供治疗性miRNA和siRNA进行靶向结肠癌治疗。我们（bin guo的小组）最近发现，miR-627是由骨化三醇诱导的，并充当了钙三醇抑制结肠癌的关键介体（胃肠病学，2013，145（2）：437-46）。我们进一步证明，miR-627靶向组蛋白脱甲基酶JMJD1A，这是一种具有生长活性的表观遗传调节剂。 miR-627和JMJD1A靶向siRNA都可以显着抑制体外和体内结肠癌的生长（裸鼠异种移植物）。我们假设，如果我们可以采用有针对性的miR-627或siRNA直接抑制JMJD1A，则可以绕过与钙相关的副作用并实现肿瘤抑制。共同投资者（Peixuan Guo）小组发现了一个异常稳定的PRNA三向连接点（3WJ）主题，可以用作脚手架来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 Nanotechnologicy，nature Nanotechnologicy，2011，6：658-67-67； Nanno； Nanano； Nanno，2012年，2012年7月25日。所得的RNA纳米颗粒具有不同的siRNA，miRNA和癌症靶向模块（例如RNA apatamer），这些模块保留了其折叠和独立的功能，用于靶向体外和体内的基因沉默和癌症。这些RNA纳米颗粒具有8 M尿素的变性性，并且在体外和体内不会在超低浓度下解离。全身注入小鼠的尾静脉已经表明它们保持完整，并且强烈与癌症结合而不积聚在肝脏，肺或其他重要器官中。与裸siRNA相比，这种纳米技术方法使RNA纳米颗粒的半衰期增加了10倍。 3WJ-PRNA纳米颗粒是无毒的，并且显示出良好的药理特征，包括生物分布，药代动力学（稳定，半寿命和清除率）和不可检测的免疫反应（Molecular Therapy，2011，11，11，19：1312-22）。该研究项目的目的是构建由RNA组成的多价纳米颗粒，以获得结肠癌治疗的增强或协同的治疗作用。我们将共轭（1）EPCAM APATMER用于靶向肿瘤抗原EPCAM或A33 SCFV，以特异性与结肠癌特异性细胞表面抗原A33的特异性结合，从而导致RNA纳米颗粒在结肠癌细胞中内部化。（2）治疗模块miR-627和/或JMJD1A siRNA，以使JMJD1A的表达保持沉默。重点是基因沉默在体内的特定肿瘤靶向和有效性，用于治疗原发性肿瘤以及转移的抑制。我们将系统地评估有关生物分布，药代动力学和免疫复杂（抗体诱导以及干扰素，TOLL样和先天性免疫组织化学，PKR效应和细胞因子诱导）的药理学特征。将评估多价RNA纳米颗粒对增强化疗的综合作用。我们相信我们的基于RNA的方法将为结肠癌带来创新的疗法。