Repurposing Mycobacterium tuberculosis tRNase toxins for cancer chemotherapy

项目摘要 引起结核病的细菌结核分枝杆菌(Mtb)的基因组中含有一种 数量惊人的专门化生长调节毒素。我们和其他人发现，许多人 其中Mtb毒素是具有高度选择性的tRNase，其性质使其成为癌症的诱因。 单独治疗或作为蛋白质结合的免疫核糖核酸酶。有一种核糖核酸酶可以进入临床试验 癌症的治疗，Onconase。然而，Mtb tRNase毒素具有比Mtb tRNase毒素更高的内在特异性 Onconase的酶活性特性不佳。这些Mtb tRNase前所未有的靶向选择性 毒素是重要的，因为早期的tRNA微阵列表达研究显示，在一些 患者来源的乳腺肿瘤样本中具有功能的全长tRNAs。这些tRNA物种被认为是 当电池被重新编程以生产一个或多个 富含这种特殊氨基酸的致癌蛋白质。因此，结核分枝杆菌核糖核酸酶毒素构成了一大新的 尚未开发的高度专门化tRNA酶的储存库，每个都具有识别单个tRNA为 底物。在这份针对FOA PAR-19-194基于微生物的癌症治疗的探索性R21提案中- 昆虫作为药物，我们假设这些特殊的毒素最终可以被利用来治疗癌症 因为它们被预测切割和禁用高效翻译致癌前基因所需的tRNA 蛋白质。这三个特定目标确定了其中六种tRNase毒素在人乳腺癌细胞中的特异性 线条和纸巾。

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.