Repurposing Mycobacterium tuberculosis tRNase toxins for cancer chemotherapy

项目摘要 导致结核病的细菌，结核分枝杆菌（Mtb）的基因组含有一种 大量的专门生长调节毒素。我们和其他人发现， 这些Mtb毒素中的一种是高度选择性的tRNase，其特性使其成为癌症的有吸引力的候选者 单独或作为蛋白质缀合的免疫RNA酶治疗。有一种核糖核酸酶可以进入临床试验 癌症治疗，Onconase。然而，Mtb tRNase毒素具有比Mtb tRNase毒素高得多的内在特异性。 Onconase的酶活性表征不佳。这些结核分枝杆菌tRNase前所未有的目标选择性 毒素是重要的，因为早期的tRNA微阵列表达研究显示，在一些 来源于患者的乳腺肿瘤样品中的功能性全长tRNA。这些tRNA被认为是 当细胞被重新编程以产生一种或多种蛋白质时， 富含这种特殊氨基酸的促癌蛋白质。因此，结核分枝杆菌tRNase毒素构成了一个新的大 未开发的高度专业化的tRNase库，每个都具有识别单个tRNA的能力， 衬底在这份针对FOA PAR-19-194微生物为基础的癌症治疗的探索性R21提案中， 我们假设这些专门的毒素最终可以用于癌症治疗 因为它们被预测切割并使有效翻译原癌基因所需的tRNA失活， proteins.这三个特异性目的定义了这些tRNase毒素中的六种在人乳腺癌细胞中的特异性。 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.