Preclinical Validation of U1 Adaptors for Suppression of KRAS in Pancreatic Cancer

U1 接头在胰腺癌中抑制 KRAS 的临床前验证

基本信息

批准号：
8979684
负责人：
Darren Richard Carpizo
金额：
$ 15.59万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-05 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8979684
关键词：
Aftercare Animal Model Arginine Aspartate Automobile Driving BCL2 gene Binding Cancer Etiology Cancer Patient Cancer cell line Cell Nucleus Cells Cessation of life Colon Complex Dendrimers Development Diagnosis Dose Drug or chemical Tissue Distribution Euthanasia Excision Fluorescence Microscopy Formulation Gene Silencing Gene Targeting Generations Genes Genetic Engineering Genetic screening method Genetically Engineered Mouse Glycine Goals Growth Health Human Human Cell Line Image Immunohistochemistry Injection of therapeutic agent KRAS2 Gene Mutation KRAS2 gene Lead Ligands Link Lung Malignant Neoplasms Malignant neoplasm of pancreas Messenger RNA Methods Modeling Molecular Genetics Morbidity - disease rate Mus Mutate Mutation Neuropilins Nude Mice Oligonucleotides Oncogenes Organ Pancreatic Adenocarcinoma Patients Penetration Peptides Pharmaceutical Preparations Proteins RGD (sequence)RNA Refractory Reporting Research Personnel Signal Transduction Site Solid Neoplasm Tail Technology Testing Therapeutic Time Tissues Toxic effect Tumor Burden Tumor Volume Ursidae Family Validation Variant Veins Western Blotting Xenograft procedure antitumor effect candidate validation chemotherapy combat design efficacy testing genomic data improved in vivo melanoma mouse model nanocarrier new technology novel oncology pancreatic cancer cells pancreatic neoplasm pre-clinical precision medicine protein expression response screening small molecule subcutaneous success targeted treatment tumor tumor growth tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Pancreatic cancer (PC) remains one of the least treatable cancers, with high metastatic propensity, poor response to existing therapies and short survivals that have not improved substantially over several decades. Most PC patients will die within the first year after diagnosis and <6% will survive five years. Currently over 40,000 new PC cases and 17,000 deaths a year are reported in the U.S. and it is expected that within a few years PC will become the third leading cause of cancer deaths. Surgical removal of the tumor is possible in less than 20% of PC patients and chemotherapy typically offers only several months of extended survival. It is widely recognized that activating mutations of the KRAS gene are key drivers of pancreatic cancer, yet the KRAS protein has proved refractory to drugging by small-molecule approaches, despite decades of effort. Two investigators on this application, Drs. Gunderson and Goraczniak, invented a new gene silencing technology called U1 Adaptors. In a large proof-of-concept study, U1 Adaptors targeting the BCL2 oncogene were recently shown to effectively suppress growth of human melanoma xenograft tumors in mice, without observable toxicity, when administered twice weekly at low dose (0.034 mg/kg). In comparison to previous generations of gene silencing oligonucleotides, U1 Adaptors are highly stable in vivo and easy to deliver selectively into diseased cells, consistent with their novel mechanism of action. We have teamed with additional investigators who bring expertise in pancreatic cancer (Dr. Carpizo) and cancer molecular genetics (Dr. Brenneman) to develop and validate anti-KRAS U1 Adaptors in mouse models of pancreatic cancer. The era of targeted therapies and personalized/precision medicine is upon us, and patient genomic data is now driving the development of novel gene-targeted therapeutics. This an arena for which U1 Adaptor technology is highly suited. U1 Adaptor gene silencing technology, through rationale design, has potential to rapidly produce potent anti-KRAS U1 Adaptor oligonucleotides that will be lead compounds for further development towards human trials. In broad terms, our specific aims are: 1) design and confirm active anti- KRAS Adaptors targeting the mouse and human KRAS genes; (2) to develop methods for highly efficient delivery of the anti-KRAS U1 Adaptors through the stroma of pancreatic tumors, using the KPC mouse as a model, and (3) to assess in-vivo efficacy in the best available mouse models of pancreatic cancer, specifically to suppress tumor growth in the mouse KPC model and in patient-derived xenografts of pancreatic cancer. Our long term goal is to develop a revolutionary pancreatic cancer therapeutic. Success in this project will also enable application of KRAS U1 Adaptors to solid tumors arising in other sites such as lung and colon.

描述（由申请人提供）：胰腺癌（PC）仍然是最难治疗的癌症之一，具有高转移倾向、对现有疗法的反应差以及生存期短且几十年来没有实质性改善。大多数 PC 患者将在诊断后第一年内死亡，<6% 的患者将存活五年。目前，美国每年报告超过 40,000 例新发 PC 病例和 17,000 例死亡，预计几年内 PC 将成为癌症死亡的第三大原因。不到 20% 的 PC 患者可以通过手术切除肿瘤，而化疗通常只能延长几个月的生存期。人们普遍认为，KRAS 基因的激活突变是胰腺癌的关键驱动因素，但尽管经过数十年的努力，KRAS 蛋白仍被证明对小分子方法的药物治疗无效。该应用程序的两名研究人员，博士。 Gunderson 和 Goraczniak 发明了一种新的基因沉默技术，称为 U1 适配器。在一项大型概念验证研究中，最近表明，以低剂量（0.034 mg/kg）每周两次给药时，针对 BCL2 癌基因的 U1 适配器可有效抑制小鼠体内人类黑色素瘤异种移植肿瘤的生长，且没有可观察到的毒性。与前几代基因沉默寡核苷酸相比，U1 接头在体内高度稳定，并且易于选择性地递送至患病细胞中，这与其新颖的作用机制一致。我们与其他具有胰腺癌（Carpizo 博士）和癌症分子遗传学（Brenneman 博士）专业知识的研究人员合作，在胰腺癌小鼠模型中开发和验证抗 KRAS U1 适配器。靶向治疗和个性化/精准医疗的时代已经来临，患者基因组数据正在推动新型基因靶向治疗的发展。 U1 适配器技术非常适合这个领域。 U1 Adapter 基因沉默技术通过原理设计，有潜力快速生产有效的抗 KRAS U1 Adapter 寡核苷酸，这些寡核苷酸将成为进一步开发人体试验的先导化合物。从广义上讲，我们的具体目标是：1）设计并确认针对小鼠和人类 KRAS 基因的活性抗 KRAS 适配器； (2) 使用 KPC 小鼠作为模型，开发通过胰腺肿瘤基质高效递送抗 KRAS U1 接头的方法，以及 (3) 评估现有最佳胰腺肿瘤小鼠模型的体内疗效癌症，特别是抑制小鼠 KPC 模型和患者来源的胰腺癌异种移植物中的肿瘤生长。我们的长期目标是开发一种革命性的胰腺癌治疗方法。该项目的成功还将使得 KRAS U1 适配器能够应用于肺和结肠等其他部位产生的实体瘤。