EXTH-01. Discovery and therapeutic exploitation of Master Regulatory miRNAs in Glioblastoma
Year: 2025
Type: article
Abstract: Glioblastoma is a fatal primary malignant brain tumor, with an average survival of only 15 months despite surgical resection, chemotherapy, and radiation therapy. Due to the concurrent deregulation of numerous genes in glioblastoma, molecular monotherapies have not improved clinical outcomes. Evidence suggests that effectively targeting multiple deregulated molecules is essential for better therapies; however, this is limited by the lack of suitable drugs and the increased toxicity of combination therapies. To address this, we hypothesized that miRNAs, small gene-regulatory RNAs that suppress multiple target gene via sequence complementarity, could be developed to inhibit multiple deregulated genes simultaneously, leading to more effective treatments. We identified master regulatory miRNAs—those that target several deregulated genes in glioblastoma—using PAR-CLIP screenings in glioblastoma cells and analyzed TCGA tumor data to find which targets were deregulated. An algorithm ranked these targets based on their significance in glioblastoma malignancy. We selected two tumor suppressor master regulatory miRNAs, miR-340 and miR-382, and one oncogenic miRNA, miR-17. Validation showed that these miRNAs target critical glioblastoma pathways and significantly inhibit cell growth, survival, invasion, and tumor growth in vivo. We developed an innovative therapeutic delivery approach using MRI-guided focused ultrasound and microbubbles, resulting in reduced tumor volume and extended survival in glioblastoma-bearing mice. This strategy offers a promising pathway for translating miRNA-based therapies into clinical trials for glioblastoma and other cancers.
Source: Neuro-Oncology
Authors: Shekhar Saha, Ying Zhang, Myron Gilbert, Collin Dube, Farina Hanif, Elizabeth Mulcahy, Sylwia Bednarek, Pawel Marcinkiewicz, Xiantao Wang, Gijung Kwak, Kadie Hudson, Yunan Sun, Manikarna Dinda, Tapas Saha, Fadila Guessous, Nichola Cruickshanks, Rossymar Colon, Lily Dell’Olio, Rajitha Anbu, Benjamin Kefas, Pankaj Kumar, Alexander Klibanov, David Schiff, Jung Soo Suk, Justin Hanes, Jamie Mata, Markus Hafner, Roger Abounader
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4416140147
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