Repurposing Mycobacterium tuberculosis tRNase toxins for cancer chemotherapy

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的 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。

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.