MicroRNA based theranostics for brain cancer: basic principles

Petrescu et al. Journal of Experimental & Clinical Cancer Research https://doi.org/10.1186/s13046-019-1180-5 (2019) 38:231 REVIEW Open Access MicroRNA based theranostics for brain cancer: basic principles George E. D. Petrescu1,2†, Alexandru A. Sabo3†, Ligia I. Torsin4, George A. Calin5,6* and Mihnea P. Dragomir5* Abstract Background: Because of the complexity of the blood-brain barrier (BBB), brain tumors, especially the most common and aggressive primary malignant tumor type arising from the central nervous system (CNS), glioblastoma, remain an essential challenge regarding diagnostic and treatment. There are no approved circulating diagnostic or prognostic biomarkers, nor novel therapies like immune checkpoint inhibitors for glioblastoma, and chemotherapy brings only minimal survival benefits. The development of molecular biology led to the discovery of new potential diagnostic tools and therapeutic targets, offering the premise to detect patients at earlier stages and overcome the current poor prognosis. Main body: One potential diagnostic and therapeutic breakthrough might come from microRNAs (miRNAs). It is wellknown that miRNAs play a role in the initiation and development of various types of cancer, including glioblastoma. The review aims to answer the following questions concerning the role of RNA theranostics for brain tumors: (1) which miRNAs are the best candidates to become early diagnostic and prognostic circulating biomarkers?; (2) how to deliver the therapeutic agents in the CNS to overcome the BBB?; (3) which are the best methods to restore/inhibit miRNAs? Conclusions: Because of the proven roles played by miRNAs in gliomagenesis and of their capacity to pass from the CNS tissue into the blood or cerebrospinal fluid (CSF), we propose miRNAs as ideal diagnostic and prognostic biomarkers. Moreover, recent advances in direct miRNA restoration (miRNA mimics) and miRNA inhibition therapy (antisense oligonucleotides, antagomirs, locked nucleic acid anti-miRNA, small molecule miRNA inhibitors) make miRNAs perfect candidates for entering clinical trials for glioblastoma treatment. Keywords: microRNA, miRNA based drugs, Antagomirs, Antisense oligonucleotides, miRNA masks, Small molecule miRNA inhibitors, miRNA mimics, Biomarkers, Glioma, Glioblastoma Background Brain and other central nervous system (CNS) tumors have an incidence of 29.4 per 100.000 persons in the adult population and 31.5% of the newly diagnosed tumors are malignant. [1]. Gliomas are tumors of the CNS arising from the glial cells. Glioblastoma (grade IV) is the most common primary malignant brain tumor (47.1%) and is characterized by a poor prognosis despite the available multimodal treatment (5.5% survival rate at 5 years) [1]. This can be explained through their heterogeneity, chemoresistance and infiltrative pattern that makes complete resection difficult. Low-grade gliomas * Correspondence: ; † George E. D. Petrescu and Alexandru A. Sabo contributed equally to this work. 5 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Full list of author information is available at the end of the article (LGG, WHO grade I-II) have better overall survival (OS) of approximately 7 years, but ultimately, they progress to high grade gliomas (HGG, WHO grade III-IV) [2]. The current standard of care protocol for glioblastoma includes maximal safe resection of the newly diagnosed lesion followed by radiotherapy and chemotherapy with temozolomide (TMZ) [3]. Regardless of this, recurrence of glioblastoma can be seen after a median of 6.9 months [4]. Bevacizumab in addition to chemo- and radiotherapy increases the progression-free survival for newly-diagnosed cases, but further studies are necessary to verify its efficiency in improving OS [3]. Due to the fulminant clinical course that HGG usually have, the diagnosis is generally too late. Unfortunately, in clinical practice, there are no blood markers that would make the early diagnosis possible [5]. The development of molecular biology led to the discovery of new potential diagnostic tools and therapeutic © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Petrescu et al. Journal of Experimental & Clinical Cancer Research (2019) 38:231 targets, offering promise to overcome the current poor prognosis and diagnose patients in earlier stages. One potential therapy is based on microRNAs (miRNAs). The majority of the human genome is transcribed into non-coding RNA (ncRNA), and only 2–3% of the genome encodes protein-genes [6]. The most studied types of ncRNAs are miRNAs. MiRNAs are a class of small ncRNAs, made of approximately 22 nucleotides [7], that are involved in gene-regulation at the posttranscriptional level by inducing mRNA degradation and translational repression. Additionally, it was shown that miRNAs have also more complex mechanisms of action: activating transcription, up regulating protein expression, interacting with RNA binding proteins, binding to Toll-like receptors and inhibiting nuclear or mitochondrial transcripts [8]. Mature miRNAs or precursor transcripts are well-known to be involved in the mechanisms of carcinogenesis [9–12] and are potential new therapeutic targets and biomarkers. This review aims to answer the following questions regarding the role of RNA theranostics for brain tumors: (1) which miRNAs are the best candidates to become early diagnostic and prognostic circulating biomarkers?; (2) how to deliver the therapeutic agents in the CNS to overcome the blood-brain barrier?; (3) which are the best methods to restore/inhibit miRNAs? Deregulation of miRNAs in brain tumors Role of miRNA dysregulation in gliomagenesis It is known that miRNAs play a role in the initiation and development of various types of cancer [13, 14]. In the past few years, the role of miRNAs in gliomagenesis has been intensely studied. They can have tumor suppressor properties or can act as oncogenes. The dysregulation of the protein complex NF-kappaB promotes tumor growth and angiogenesis in glioblastoma [15, 16]. The tumor suppressive miR-31 that targets TNF receptor associated death domain (TRADD) and inhibits NF-kappaB activation is deleted in the majority of HGGs and therefore tumor proliferation is increased [17]. MiR-16 also downregulates the NF-kappaB1/MMP9 pathway and is less expressed in glioma samples [18]. The same study found that m (...truncated)