Malignant brain tumors of glial origin remain today as a serious clinical and scientific problem as ever. Patients with the most malignant glioma, glioblastoma, have an average survival time of less than one year. Like other cancers, gliomas are diseases caused by dysregulated cell proliferation, differentiation, migration and death. However, molecular events that lead to dysregulation of these key processes are not well understood. How gene expression is controlled in tumor formation will be a critical issue in understanding the biology of these tumors. Recently, a novel class of small regulatory molecules, microRNA (miRNA), has been implicated in post-transcriptional regulation of gene expression in a wide range of cancers. A number of miRNAs are aberrantly expressed in gliomas, and some of them may regulate expression of important oncogenes and tumor suppressors. The overall goal of this proposal is to validate miRNAs playing a functional role in human glioma formation and to elucidate intracellular signaling pathways that mediate functions of these miRNAs. To achieve this goal, selected oncogenic miRNAs will be inhibited in glioma cells and effects of these manipulations on in vitro and in vivo parameters of glioma growth will be examined. Since miRNA inhibition may potentially produce various off-target effects, Specific Aim 1 will involve validation of highly specific oligonucleotide inhibitors for the miRNAs of interest. Using these specific tools, we will validate key mRNA targets that mediate miRNA functions in glioma cells.
In Specific Aim 2 we will determine effects of the miRNAs on glioma cell viability, proliferation, and apoptosis in vitro.
In Specific Aim 3, using ex vivo and in vivo approaches, we will further determine effects of the miRNAs and most potent miRNA combinations on growth and invasion of intracranial glioma tumors in animal models. The proposed work promises to yield significant new insights into the biology of glioma, and more generally - gene expression in cancer, and may validate a novel class of molecular targets for glioma therapy.
Despite very aggressive treatments, survival for patients diagnosed with malignant brain tumor, glioblastoma, has only marginally changed over the past 25 years. There is a critical need for new molecular targets, concepts and approaches to treat this devastating disease. Recently discovered small regulatory RNA molecules, known as microRNAs, regulate molecular events involved in tumor formation in the brain. The proposed work on microRNAs holds promises to advance our understanding of brain tumors and may open the door to novel treatments.
| Yanachkov, Ivan; Zavizion, Boris; Metelev, Valeri et al. (2017) Self-neutralizing oligonucleotides with enhanced cellular uptake. Org Biomol Chem 15:1363-1380 |
| El Fatimy, Rachid; Subramanian, Shruthi; Uhlmann, Erik J et al. (2017) Genome Editing Reveals Glioblastoma Addiction to MicroRNA-10b. Mol Ther 25:368-378 |
| Teplyuk, Nadiya M; Uhlmann, Erik J; Gabriely, Galina et al. (2016) Therapeutic potential of targeting microRNA-10b in established intracranial glioblastoma: first steps toward the clinic. EMBO Mol Med 8:268-87 |
| Teplyuk, Nadiya M; Uhlmann, Erik J; Wong, Andus Hon-Kit et al. (2015) MicroRNA-10b inhibition reduces E2F1-mediated transcription and miR-15/16 activity in glioblastoma. Oncotarget 6:3770-83 |
| Godlewski, Jakub; Krichevsky, Anna M; Johnson, Mark D et al. (2015) Belonging to a network--microRNAs, extracellular vesicles, and the glioblastoma microenvironment. Neuro Oncol 17:652-62 |
| Wong, Hon-Kit Andus; Fatimy, Rachid El; Onodera, Courtney et al. (2015) The Cancer Genome Atlas Analysis Predicts MicroRNA for Targeting Cancer Growth and Vascularization in Glioblastoma. Mol Ther 23:1234-1247 |
| Teplyuk, Nadiya M; Mollenhauer, Brit; Gabriely, Galina et al. (2012) MicroRNAs in cerebrospinal fluid identify glioblastoma and metastatic brain cancers and reflect disease activity. Neuro Oncol 14:689-700 |
| Sonntag, Kai C; Woo, Tsung-Ung W; Krichevsky, Anna M (2012) Converging miRNA functions in diverse brain disorders: a case for miR-124 and miR-126. Exp Neurol 235:427-35 |
| Gabriely, Galina; Teplyuk, Nadiya M; Krichevsky, Anna M (2011) Context effect: microRNA-10b in cancer cell proliferation, spread and death. Autophagy 7:1384-6 |
| Gabriely, Galina; Yi, Ming; Narayan, Ravi S et al. (2011) Human glioma growth is controlled by microRNA-10b. Cancer Res 71:3563-72 |
