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：
8809378
负责人：
Darren Richard Carpizo
金额：
$ 20.33万
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/8809378
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 Data Dendrimers Development Diagnosis Dose Drug Formulations Drug or chemical Tissue Distribution Euthanasia Excision Fluorescence Microscopy Gene Silencing Gene Targeting Generations Genes Genetic Engineering Genetic screening method Genetically Engineered Mouse Genomics Glycine Goals Growth 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 improved in vivo melanoma mouse model nanocarrier new technology novel oncology pancreatic cancer cells pancreatic neoplasm pre-clinical precision medicine protein expression public health relevance response screening small molecule subcutaneous success targeted treatment tumor tumor growth tumor xenograft

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 Data Dendrimers Development Diagnosis Dose Drug Formulations Drug or chemical Tissue Distribution Euthanasia Excision Fluorescence Microscopy Gene Silencing Gene Targeting Generations Genes Genetic Engineering Genetic screening method Genetically Engineered Mouse Genomics Glycine Goals Growth 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 improved in vivo melanoma mouse model nanocarrier new technology novel oncology pancreatic cancer cells pancreatic neoplasm pre-clinical precision medicine protein expression public health relevance response screening small molecule subcutaneous success targeted treatment tumor tumor growth tumor xenograft

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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）仍然是最不可治疗的癌症之一，具有高转移性倾向，对现有疗法的反应不佳和短期生存的疾病，这些癌症在几十年中没有大幅改善。诊断后的第一年，大多数PC患者将死亡，<6％的患者将存活五年。目前，在美国报告了超过40,000例新的PC病例和每年17,000例死亡，预计PC将在几年内成为癌症死亡的第三大主要原因。在不到20％的PC患者中，可以手术切除肿瘤，而化疗通常仅提供几个月的延长生存期。人们普遍认识到，Kras基因的激活突变是胰腺癌的关键驱动因素，但是尽管努力了数十年，KRAS蛋白已证明对小分子方法的吸毒难治性。两名有关此应用程序的调查人员，博士。 Gunderson和Goraczniak发明了一种名为U1适配器的新基因沉默技术。在一项大型概念验证研究中，靶向BCl2癌基因的U1适配器最近显示可有效抑制小鼠中人类黑色素瘤异种移植肿瘤的生长，而每周在低剂量下进行两次施用，而没有可观察到的毒性（0.034 mg/kg）。与前几代基因沉默的寡核苷酸相比，U1衔接子在体内高度稳定，易于选择性地输送到患病的细胞中，这与它们的新型作用机理一致。我们已经与其他研究人员合作，他们在胰腺癌（Carpizo博士）和癌症分子遗传学（Brenneman博士）中提供了专业知识，以开发和验证胰腺癌小鼠模型中的抗Kras U1适配器。靶向疗法和个性化/精确药物的时代正在我们身上，并且患者基因组数据现在正在推动新型基因靶向治疗的发展。这是U1适配器技术非常适合的舞台。 U1适配器基因沉默技术通过基本原理设计有可能快速生产有效的抗Kras U1适配器寡核苷酸，这将成为进一步发展人类试验的铅化合物。从广义上讲，我们的具体目的是：1）设计并确认针对小鼠和人类KRAS基因的主动抗Kras适配器； (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.我们的长期目标是开发一种革命性的胰腺癌治疗。该项目的成功还将使KRAS U1适配器应用于在肺和结肠等其他部位产生的实体瘤。