Novel extra cellular RNA-based combinatorial RNA inhibition therapy

基于细胞外RNA的新型组合RNA抑制疗法

基本信息

批准号：
8962199
负责人：
George A Calin
金额：
$ 99.95万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8962199
关键词：
Affect Animal Model Ascites Biological Assay Biology Buffers Cancer Center Cancer Patient Cancer cell line Categories Cause of Death Cell model Cells Clinical Trials Code Development Disease Dose Drug Kinetics Drug or chemical Tissue Distribution Endocrine Endpoint Determination Environment Extracellular Space Genes Goals Grant Gynecologic Health Hormones Human In Vitro Innovative Therapy Lead Libraries Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of ovary Measurement Medical Methods MicroRNAs Modeling Mus Names Oncogenic Organism Outcome Ovarian Ovarian Carcinoma Pathway interactions Patients Pharmacology Phase Phenotype Plasma Play Procedures Production Protocols documentation RNA Research Research Project Grants Role Safety Sampling Schedule Scientist Serous Signal Pathway Signal Transduction Small Interfering RNA Small RNA Technology Testing Therapeutic Time Tissues Treatment Efficacy Tumor Suppressor Proteins Tumor-Derived Untranslated RNA Validation Vesicle Work base calin cancer cell cancer therapy cancer type clinical practice combinatorial deep sequencing design dosage extracellular genome-wide analysis improved in vivo innovation model design mortality nanoliposome nanoparticle new technology novel novel therapeutic intervention pre-clinical preclinical study safety study therapeutic development time use treatment effect tumor uptake

项目摘要

DESCRIPTION (provided by applicant): RNA molecules are secreted in extracellular spaces (exRNAs) and act as endocrine signals altering the phenotypes of cancer cells. In this application we will focus on the class of small non-codingRNAs named microRNAs. We propose an innovative therapeutic concept: the depletion of oncogenic microRNAs from malignant cells by enhancing their secretion as exRNAs or blocking suppressor microRNAs' delivery in extracellular space by blocking secretion mechanisms. Our main goal is to develop new strategies using combined miRNA and siRNA to maximize therapeutic benefit by affecting the production of exRNAs. Our proposal centers on the identification and targeting of specific tumor-derived exRNA and exosomes leading to novel therapies and improved therapeutic outcomes. In UH2 phase of the grant, using ovarian cancer (OC) cell lines and cells derived from OC patient tumors, we will identify novel exRNA-based cancer therapeutic lead candidates by siRNA library genome-wide screening based on secretion measurements, by small RNA deep sequencing in "paired" samples from tumors, plasma and ascites from the same patient, and by functional studies for the lead exRNA candidates. In the UH3 phase, we will achieve pre-clinical optimization by testing the exRNA lead(s) identified in the UH2 for antitumor efficacy in well-established OC murine orthotopic models and their safety using well-established preclinical protocols. The aims in exploratory UH2 phase are designed to identify and validate the function of novel exRNA therapeutic candidates for pre- clinical studies. In UH3 phase, we will formulate the methods for the validation of the assays to determine the activity, pharmacology in tissue and plasma to establish dosage schedules in animal models for the design of rational anti-tumor approaches. Using our nanoliposomal delivery technology, we will also conduct target modulation and efficacy studies to generate clear evidence regarding the safety of exRNA-based therapeutic candidates in the proposed dose range. Our approach, by using a new category of regulatory exRNAs- miRNAs, could substantially enhance therapeutic efficacy for cancer treatment. We will also demonstrate, for the first time, the use of nanoliposome-siRNA-exRNA targeting to generate a synergistic boosting effect for treatment of cancers. While we are focusing on OC due to the high mortality associated with this malignancy, our findings have applications for any type of cancer. This proposal brings synergistic capabilities of scientists working for over a decade in the fields of miRNA (Dr. Calin), siRNA (Dr. Sood), nanoparticle delivery (Dr. Lopez-Berestein), and exosome biology (Dr. O'Halloran). The team has the expertise and synergistic drive to achieve novel exRNA therapeutic development by performing highly innovative research, and has developed RNA-based therapies in the past.

描述（由申请人提供）：RNA分子在细胞外空间（exRNA）中分泌，并充当改变癌细胞表型的内分泌信号。在此应用中，我们将重点关注称为 microRNA 的小型非编码 RNA。我们提出了一个创新的治疗概念：通过增强 exRNA 的分泌来消除恶性细胞中的致癌 microRNA，或者通过阻断分泌机制来阻断抑制性 microRNA 在细胞外空间的传递。我们的主要目标是开发使用组合 miRNA 和 siRNA 的新策略，通过影响 exRNA 的产生来最大限度地提高治疗效果。我们的提案集中于识别和靶向特定的肿瘤来源的 exRNA 和外泌体，从而带来新的疗法和改善的治疗结果。在资助的 UH2 阶段，使用卵巢癌 (OC) 细胞系和源自 OC 患者肿瘤的细胞，我们将通过基于分泌测量的 siRNA 文库全基因组筛选、小 RNA 深度筛选来确定基于 exRNA 的新型癌症治疗先导候选药物。对来自同一患者的肿瘤、血浆和腹水的“配对”样本进行测序，并对主要 exRNA 候选物进行功能研究。在 UH3 阶段，我们将通过测试 UH2 中确定的 exRNA 先导化合物在成熟的 OC 小鼠原位模型中的抗肿瘤功效及其使用成熟的临床前方案的安全性来实现临床前优化。探索性 UH2 阶段的目标旨在识别和验证用于临床前研究的新型 exRNA 治疗候选药物的功能。在UH3阶段，我们将制定验证测定的方法，以确定组织和血浆中的活性、药理学，从而在动物模型中建立剂量方案，以设计合理的抗肿瘤方法。利用我们的纳米脂质体递送技术，我们还将进行靶标调节和功效研究，以生成有关基于 exRNA 的候选治疗药物在建议剂量范围内安全性的明确证据。我们的方法通过使用一类新的调节性 exRNA-miRNA，可以显着提高癌症治疗的疗效。我们还将首次展示使用纳米脂质体-siRNA-exRNA靶向来产生癌症治疗的协同增强效应。虽然由于 OC 与这种恶性肿瘤相关的高死亡率，我们将重点放在 OC 上，但我们的研究结果适用于任何类型的癌症。该提案带来了在 miRNA（Calin 博士）、siRNA（Sood 博士）、纳米颗粒递送（Lopez-Berestein 博士）和外泌体生物学（O'Halloran 博士）领域工作了十多年的科学家的协同能力。。该团队拥有专业知识和协同动力，通过开展高度创新的研究来实现新型 exRNA 治疗的开发，并在过去开发了基于 RNA 的疗法。