Repurposing Mycobacterium tuberculosis tRNase toxins for cancer chemotherapy

重新利用结核分枝杆菌 tRNase 毒素进行癌症化疗

基本信息

批准号：
10532244
负责人：
NANCY ANN WOYCHIK
金额：
$ 18.06万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10532244
关键词：
Amino Acids Anticodon Antineoplastic Agents Bacteria Breast Breast Cancer cell line Cancer Etiology Cancer cell line Cell Line Cells Cessation of life Chemotherapy-Oncologic Procedure Clinical Treatment Clinical Trials Codon Nucleotides Death Rate Effectiveness Endocytosis Endowment Enzymes Exhibits Foundations Genome Goals Growth Human Immune response Individual Laboratories Length Lysine Lysine-Specific tRNA MCF10A cells MCF7 cell Malignant - descriptor Malignant Neoplasms Malignant mesothelioma Mammary Gland Parenchyma Mammary Neoplasms Messenger RNA Methods Monitor Mycobacterium tuberculosis Non-Malignant Non-Small-Cell Lung Carcinoma Oncogenic Onconase Patients Pharmaceutical Preparations Phase Physiology Population Property Proteins RNA Resistance Ribonucleases Ribosomes Sampling Specificity System Tetracyclines Therapeutic Tissues Toxin Transfer RNA Translating Translations Tuberculosis Virulence Woman breast cancer survival cancer cell cancer therapy cytotoxic cytotoxicity experimental study innovation malignant breast neoplasm microbial novel strategies overexpression pancreatic neoplasm pathogen pressure ranpirnase recruit response stable cell line targeted cancer therapy transcriptome sequencing triple-negative invasive breast carcinoma tumor

项目摘要

Project Summary The genome of the bacterium that causes tuberculosis, Mycobacterium tuberculosis (Mtb), harbors an astonishingly large number of specialized growth regulating toxins. We and others have discovered that many of these Mtb toxins are highly selective tRNases with properties that make them attractive candidates for cancer treatment on their own or as protein-conjugated immunoRNases. There is one RNase to go into clinical trials for treatment of cancer, Onconase. However, the Mtb tRNase toxins have much higher intrinsic specificity than the poorly characterized enzymatic activity of Onconase. The unprecedented target selectivity of these Mtb tRNase toxins is important because earlier tRNA microarray expression studies revealed significant increases in a few functional, full length tRNAs in patient-derived breast tumor samples. These tRNA species are thought to be upregulated in order to accommodate higher demand when cells are reprogrammed to produce one or more cancer-promoting proteins rich in this particular amino acid. Therefore, Mtb tRNase toxins constitute a large new untapped reservoir of highly specialized tRNases, each endowed with the ability to recognize a single tRNA as substrate. In this exploratory R21 proposal in response to FOA PAR-19-194 Microbial-based Cancer Therapy - Bugs as Drugs, we hypothesize that these specialized toxins can ultimately be exploited for cancer treatment because they are predicted to cleave and disable tRNAs required for efficient translation of pro-oncogenic proteins. The three specific Aims define the specificity of six of these tRNase toxins in human breast cancer cell lines and tissues.

项目概要引起结核病的细菌结核分枝杆菌 (Mtb) 的基因组包含一个数量惊人的专门生长调节毒素。我们和其他人发现，许多这些 Mtb 毒素是高度选择性的 tRNA 酶，其特性使其成为有吸引力的癌症候选者单独治疗或作为蛋白质缀合的免疫RNA酶进行治疗。有一种 RNase 进入临床试验治疗癌症，Onconase。然而，Mtb tRNase 毒素比 Mtb tRNase 毒素具有更高的内在特异性。 Onconase 的酶活性特征不明确。这些 Mtb tRNase 具有前所未有的靶标选择性毒素很重要，因为早期的 tRNA 微阵列表达研究表明，一些患者来源的乳腺肿瘤样本中的功能性全长 tRNA。这些 tRNA 种类被认为是当细胞被重新编程以产生一种或多种时，上调以适应更高的需求富含这种特殊氨基酸的促癌蛋白质。因此，Mtb tRNase毒素构成了一个巨大的新毒素。未开发的高度专业化 tRNA 库，每种 tRNA 都具有识别单个 tRNA 的能力基材。在这个响应 FOA PAR-19-194 基于微生物的癌症治疗的探索性 R21 提案中 - 虫子作为药物，我们假设这些特殊的毒素最终可以用于癌症治疗因为它们预计会裂解并禁用有效翻译促癌基因所需的 tRNA 蛋白质。这三个具体目标定义了人乳腺癌细胞中六种 tRNase 毒素的特异性线和组织。